WO2014045065A2 - Dietary compositions and their uses - Google Patents
Dietary compositions and their uses Download PDFInfo
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- WO2014045065A2 WO2014045065A2 PCT/GB2013/052487 GB2013052487W WO2014045065A2 WO 2014045065 A2 WO2014045065 A2 WO 2014045065A2 GB 2013052487 W GB2013052487 W GB 2013052487W WO 2014045065 A2 WO2014045065 A2 WO 2014045065A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carnitine
- composition according
- dietary composition
- muscle
- leucine
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/175—Amino acids
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2250/00—Food ingredients
- A23V2250/02—Acid
- A23V2250/06—Amino acid
- A23V2250/0612—Carnitine
Definitions
- the present invention relates to dietary compositions and their use in improving body composition, e.g. reducing body fat and/or increasing lean mass, improving health and treating certain conditions .
- the body's carnitine; store is found almost exclusively in skeletal muscle, where it plays an essential role in the transport of fat into the body's mitochondria so it can then be used for energy production.
- the muscle total carnitine pool is about 25 mmol/kg dry muscle, and is known to be vital in dictating the proportions of fat and carbohydrate used by muscle for energy production during exercise and at high exercise intensities, the availability of free carnitine limits fat oxidation for energy production.
- increasing skeletal, muscle free carnitine through supplementation prevents the build-up of lactic accumulation in muscle delaying the onset of muscle fatigue, increases fat oxidation at nil/low to medium intensity exercise and increases the
- the body's store of creatine is found in muscle, where it plays a fundamental role in maintaining energy production during exercise.
- the total creatine store (phosphocreatine and free creatine) in healthy, non-vegetarian, subjects is about 124 mmol/kq dry muscle, but it can vary widely between individuals (100-150 mmol/kg dry muscle) .
- Dietary creatine supplementation at a. rate of 20g er day for 5 days has been shown to increase muscle total creatine content on average by 20%. A similar, but more gradual, increase is obtained when creatine is ingested at a rate of 2 to 5g per day for about a month.
- creatine supplementation has become enormously popular in athletes wishing to improve athletic performance in snort duration, very high intensity sports. It is also possible that creatine supplementation may be of therapeutic benefit to patients wi h muscular and neurological disorders.
- Exercise intensity and duration are two major factors that affect whether muscle uses carbohydrate and/or fat during exercise to cover the energy costs of that exercise. As exercise intensity increases and the duration decreases ? the predominant fuel becomes carbohydrate. Conversely, as exercise intensity decreases and the duration increases, the predominant fuel becomes fat. The maximal competition between these two main energetic substrates to enter oxidative pathways seems to occur at -75% of maximal oxygen consumption (V0 2mil ) .
- the predominant fuel is fat. Since the human body has relatively large reserves of fat it is unlikely that fat availability would limit the performance at such work levels. As exercise intensity increases and carbohydrate becomes the predominant fuel the human body's limited carbohydrate stores (mainly in the form of glycogen) causes the duration of the physical effort at intensities between 60-85% of our VO ⁇ x to decline correspondingly and the exhaustion time usually matches the point at which muscle glycogen reserves are depleted .
- the present invention provides products and methods for activating fatty oxidation in skeletal muscle, inter alia, by enhancing uptake by muscle of carnitine and/or creatine, and/or increasing the cellular coenzyme A (CoASH) pool.
- the present inventor has surprisingly found that a low carbohydrate (and therefore potentially low calorie) composition incorporating specific free amino acids, such as L-leucine and L-phenylalanine, provide enhanced carnitine uptake by skeletal muscle.
- the present invention provides a dietary composition comprising: a carnitine source; a carbohydrate source; a protein source; and one or more free amino acids.
- said one or more free amino acids comprise:: ⁇ i) L-leucine or a salt or derivative: thereof; and/or (ii) L-phenylalanine or a salt or derivative thereof.
- the present invention provides, in one aspect, a dietary composition compri sing :
- the free L-leucine or salt or amino acid derivative thereof may, for example, be selected from the group consisting of: L-leucine, leucine alpha ketoglutarate (AKG) , leucine ethyl ester, -acetyl- leucine and nor-leucine salt.
- the free L-phenylalanine or salt or amino acid derivative thereof may, for example, be selected from the group consisting of: L- phen lala i e, phe ylalanine alpha ketogluta ate, phen lalanine ethyl ester and N-acetyl-phenylalanine .
- the composition comprises both L-leucine and L-phenylalanine.
- L-leucine is present in an amount within the range 0,1 to 9.0 g per g of carnitine, for example, within the range 0.2 to 7.5 g per g of carnitine or within the range 1 to 6 g per g of carnitine. In certain cases L-leucine is present at about. 1.44 g per g of carnitine .
- L- phenylalanine is present in an amount within the range 0.1 to 9.0 g per g of carnitine, for example within the range 0.2 to 7.5 g per g of carnitine or within the range 1 to 6 g per g of carnitine. In certain cases L-phenylalanine is present at. about 1.44 g per g of carnitine .
- one or more servings for example a course of dietary
- composition of the invention is effective to enhance carnitine accumulation in skeletal muscle, liver and/or kidney tissue in a mammalian subject. It. is particularly advantageous that, the presence of certain amino acids such as L-leucine and/or L-phenylalanine, stimulates an insulin-dependent carnitine uptake into muscle without the need for a sugar-induced insulin spike. This allows the muscle carnitine enhancement, to be achieved 'without requiring excessive carbohydrate supplementation and the unwanted e cess calorie load that such carbohydrate supplementation would entail.
- certain amino acids such as L-leucine and/or L-phenylalanine
- compositions of the present, invention on sugar-induced insulin spike is especially advantageous in the context of individuals who exercise only moderately or not at all because excess carbohydrate may not be wanted.
- the ability of the enhanced muscle carnitine levels to stimulate greater fatty acid oxidation mitigates a carbohydrate calorie load such that even when a composition of the present invention includes significant carbohydrate, the net effect of the composition may be "zero calorie" in terms of its effect on body fat.
- the dietary composition may further comprise creatine or a salt thereof.
- creatine is present in an amount within the range 0.1 to 9.0 g per g of carnitine. In certain cases, creatine is present at about 1:1 ratio by weight, to carnitine.
- one or more servings for example a course of dietary supplementation over a period of days or weeks
- the composition of the invention may be effective to enhance creatine accumulation in skeletal muscle in a. mammalian sub ect .
- the present invention provides a dietary composition comprising D-pantothenic acid and L-cysteine.
- the composition thereby provides coenzyme A (CoASH) precursors such that the CoASH pool within muscle: of a subject may be enhanced.
- CoASH coenzyme A
- D-pantothenic acid is present in an amount within the range 0.05 g to 5 g.
- L ⁇ cysteine is present in an amount within the range 0.05 g to 5 g.
- one or more servings of the composition may be effective to enhance coenzyme A accumulation in muscle tissue in a mammalian subject .
- the present invention provides a dietary composition in accordance with the first aspect of the invention which further comprises D- pantothenic acid and L-cysteine.
- D-pantothenic acid is present in an amount within the range 0.05 g to 5 g per g of carnitine.
- L-cysteine is present in an amount within the range 0.05 g to 5 g.
- one or more servings ⁇ for example a course of dietary supplementation over a period of days or weeks) of the composition of the first aspect of the present invention may be effective to enhance both coenzyme A accumulation and carnitine accumulation, and. in certain cases creatine accumulation, in muscle tissue in a mammalian subject.
- the dietary composition may further comprise at least, one carbohydrate.
- the at least one carbohydrate comprises a polysaccharide such as Vitargo®.
- the at. least one carbohydrate comprises a carbohydrate selected from the group consisting of: glucose, maltose, sucrose, galactose and. lactose.
- the amount of carbohydrate may be within the range 0.1 to 9.0 g per g of carnitine.
- the dietary composition in accordance with any aspect of the present invention is provided in the form of a low carbohydrate serving having not more than 3 g carbohydrate per g of carnitine.
- the dietary composition may further comprise at least one protein.
- the amount of protein is in the range 0.1 to 9.0 g per g of carnitine, for example, in the range 0.2 to 7.5 g per g of carnitine or in the range 1 to 6 g per g of carnitine.
- the dietary composition in accordance with any aspect of the present invention comprises whey protein, for example, whey protein hydrolysate ( PH) , Additionally or alternatively, the dietary composition may comprise soy protein.
- the dietary composition may be provided in the form of a serving having less than 30 calories derived from carbohydrates, protein and naturally occurring free amino acids per g of carnitine and, if present, creatine. Specifically contemplated herein are truly "low calorie" servings that avoid or minimise empty calories.
- the dietary composition may be provided in the form of a serving having not more than 3 g of fat.
- the dietary composition may further comprise one or more ⁇ such as two, three, four or five or more) of the following: amylopectin barley starch, alpha-lipoic acid ("ALA"), maltodextrin, dextrose, WPC-80, one or more flavourings, colouring, citric acid, potassium citrate, L ⁇ taurine, chromium, 4-hydroxyisoleucine and sucralose.
- ALA alpha-lipoic acid
- ALA alpha-lipoic acid
- he p esent inve tion provides an article of manufacture comprising packaging housing a plurality of discrete servings of the dietary composition in accordance with any one of the first or second aspects of the invention and, optionally, a label or insert with instructions regarding dose and or frequency of said servings.
- the present invention provides a food or drink product incorporating the dietary composition in accordance with any ⁇ one of the first or second aspects of the invention.
- the present invention provides a dietary supplement
- the present invention provides a dietary composition in accordance with any one of the first or second aspects of the invention for use in a method of treatment of obesity, metabolic syndrome, muscle wasting, diabetes, sarcopenia, degenerative disease and/or muscle fatigue in a mammalian subject.
- the present invention provides a method of treatment of a mammalian subject having obesity, metabolic syndromes, muscle wasting, diabetes, sarcopenia, degenerative disease and/or muscle fatigue, said method comprising administering a dietary composition in accordance with any one of the first or second aspects of the invention to the mammalian subject in need thereof.
- the present invention provides use of a dietary composition in accordance with any one of the first or second aspects of the invention in the supplementation of a vegetarian diet of a mammalian subject.
- the present invention provides a method of enhancing athletic performance of a mammalian subject, comprising administration of one or more servings of the dietary composition in accordance with any one of the first or second aspects of the invention to the subject.
- the present invention provides a method of reducing absolute body fat and/or relative body fat per unit of lean body mass, or of preventing gain in absolute or relative body fat, comprising administration of one or more servings of the dietary composition in accordance with any one of the first, or second aspects of the invention to the subject.
- the mammalian subject may be a human or a domestic, working or companion animal (e.g. a dog, cat, horse, including a race horse) .
- a domestic, working or companion animal e.g. a dog, cat, horse, including a race horse
- the subject is a human.
- a wide cross-section of human sub ects are specifically contemplated.
- the subject may be an athlete, a vegetarian, an aged person (e.g. of greater than 60 or 70 or 80 years of age) , an overweight or obese person (e.g. Body mass index (BMI) of >25, >30 or >35) .
- BMI Body mass index
- the human subject may be of generally good health or may be suffering from a condition selected from: obesity, metabolic syndrome, muscle wasting, diabetes, sarcopenia, degenerative disease and/or muscle fatigue.
- the present invention provides a method for producing a dietary composition in accordance with any one of the first or second aspects of the invention, comprising:
- a carnitine source and one or both of: (i) a source of leucine, or a salt or derivative thereof, and (ii) a source of phenylalanine, or a salt or derivative thereof;
- the method in accordance with this aspect of the present invention may further comprise providing and mixing with the other ingredients one or more (such as two, three, four or five or more) of the following: creatine, D ⁇ pantothenic acid, L--cysteine, carbohydrate, vitargo®, glucose, protein, whey protein hydrolysate, soy protein, amylopectin barley starch, alpha-lipoic acid ( "ALA” ) , maltodextrin, dextrose, WPC-80, flavour, citric acid, potassium citrate,
- the other ingredients one or more (such as two, three, four or five or more) of the following: creatine, D ⁇ pantothenic acid, L--cysteine, carbohydrate, vitargo®, glucose, protein, whey protein hydrolysate, soy protein, amylopectin barley starch, alpha-lipoic acid ( "ALA” ) , maltodextrin, dextrose, WPC
- the method comprises the steps:
- amylopectin barley starch dextrose, high quality milk proteins, L-phenylalanine and L-leucine;
- the present invention provides a method for producing a food or drink product, comprising the step of incorporating the dietary composition in accordance with any one of the first or second aspects of the invention into a food or drink mixture at a stage prior to the final packaging of the food or drink mixture to form the end food or drink product .
- the food or drink product is selected from the group consisting of: a soup, a pasta sauce, a cereal bar, a milkshake pre-- mix, a. breakfast cereal and a sports drink.
- the final food, or drink product may, in certain cases, include carbohydrate and/or fat at a level above; that contemplated for certain embodiments of the dietary composition of the present invention, it is envisaged that the fat burning effect of the carnitine enhancement achieved by the technology of the present invention mitigates or nullifies the potential fat gain that would otherviise be induced by excess consumption of calorie-rich ingredients of the final food or drink product, such as carbohydrate (the so-called "zero calorie” effect.) .
- Figure 1 shows the experimental protocol employed in the coenzyme A precursor supplementation studies. Cycling exercise at 75% V0 2 max for approximately 90 mins . Is followed by a work output pe formance; test. Muscle samples were taken at the indicated time points (broad arrows; 0, 60 and 90 mins.); blood and expired gas samples were taken at the indicated time points (narrow arrows) .
- Figure 2 shows a graph of heart rate (bpm) for pre-placebo (open circles), pre-supplementation ⁇ open squares), post-placebo (filled circles) and post-supplementation (filled squares), plotted against exercise time.
- Figure 3 shows a graph of plasma insulin response plotted against time for subjects having taken whey protein (WPI; open triangles) or whey protein hydrolysate (WPH; filled squares) .
- WPI whey protein
- WPH whey protein hydrolysate
- Figure 4 shows fat mass in kg for control subjects (left hand bars) at 0 and at 12 weeks of twice-daily carbohydrate supplementation
- a low caloric supplement comprising a carnitine source, a protein source, a carbohydrate source and one or more naturally occurring free amino acids wherein a serving of the low carbohydrate carnitine./ creatine supplement is effective in amplifying carnitine accumulation in skeletal muscle, liver and/or kidney tissue.
- Also provided in accordance with the present invention is a method for manufacturing a low caloric supplement, comprising the step of mixing a carnitine source, a carbohydrate source, a protein source and. a naturally occurring free amino acid, blending and mixing for 20 minutes; and checking for uniformity/homogeneity and. then aliquoting into a serving.
- the present invention may in some cases enable dietary supplements for vegetarians who are now known to have reduced skeletal carnitine transport capacity compared to non-vegetarians specifically for improving the health of vital organs such as heart, kidney and liver in humans.
- the present invention also providesaloo: a method of supplementing the diet of an animal, comprising administering to the animal a serving of a low caloric supplement comprising carnitine,
- the present invention also provides a supplemental dietary supplement
- composition that may include L-Leucine, including salts or
- L-phenylalanine including salts or derivatives thereof, carnitine and/or, including salts or derivatives thereof, and may also include sources of dietary protein and/or
- the supplemental dietary composition may also include one or more of Amylopectin barley starch, dextrose, alpha-lipoic acidC'ALA”), maltodextrin, WPC-80, bitter blocker flavours, citric acid, more flavour, potassium citrate, and sucralose.
- Amylopectin barley starch dextrose, alpha-lipoic acidC'ALA
- maltodextrin WPC-80
- bitter blocker flavours citric acid, more flavour, potassium citrate, and sucralose.
- supplemental dietary composition may activate the protein synthesis machinery and deactivate catabolic processes within skeletal muscle by regulating molecular signals to control anabolic and anti- catabolic activity in skeletal muscle.
- the supplemental dietary composition may stimulate fatty oxidation, decrease muscle catabolism and improve body composition, treat muscle wasting or degenerative disease, suppress the effects of sarcopenia in the aging population a d/or provide a beneficial effect by influenci g the genetic control system for global protein synthesis.
- the present invention provides a low caloric supplement comprising; ca nitine, carbohydrate, protein and naturally occur ing free amino acids wherein a serving of the supplement is effective in increasing carnitine accumulation in skeletal muscle.
- the present invention also provides for a method of increasing carnitine accumulation in skeletal muscle of an animal comprising the steps of: administering a low carbohydrate carnitine supplement comprising a serving of carnitine, carbohydrate, protein and one more naturally occurring free amino acids; and increasing the total muscle carnitine in the skeletal muscle of an animal.
- the present invention relates to a method of
- a low caloric supplemental dietary composition that may activate the protein, synthesis machinery and deactivate catabolic processes within skeletal muscle by regulating molecular signals to control anabolic and anti-catabol ic activity in skeletal muscle, and/or provide a beneficial effect by influencing the genetic control system for global protein synthesis and may also stimulate fatty oxidation, decrease muscle catabolism, treat muscle wasting or degenerative disease, suppress the effects of sarcopenia i he aging population, and improve vital organ health in
- the method of manufacturing a supplemental dietary composition includes the step of mixing one or more of L-Leucine, including salts or derivatives thereof, L-phenylalanine, including salts or derivatives thereof and carnitine including salts or derivatives thereof.
- the method of manufactureng a supplemental dietary composition may also include the step of mixing one or more of Amylopectin barley starch, dextrose, ALA, maltodextrin, WPC-80, bitter blocker flavour, citric acid, another flavour, potassium citrate, sucralose and colou ing.
- the present invention also provides for a method for manufacturing a low caloric supplement comprising; carnitine, carbohydrate, protein and a naturally occurring free amino acid the method comprising the following steps: premixing microcrystalline cellulose with the following ingredients to the premix; carnitine, Amylopectin barley starch, dextrose, high quality milk proteins, L-Phenylalanine , L ⁇ Leucine, and microcrystalline cellulose; adding magnesium stearate and silica which had been pre-sifted; blending and mixing for 20 minutes; and checking for uniformity/homogeneity and then aliquoting into a serving.
- supplementation is believed to have an additive effect on changing body composition e.g. weight loss and athleticism by the addition of lean mass and reduction of fat mass.
- Leucine, Leucine alpha ketoglutarate (AKG) Leucine ethyl ester, N-acetyl --leucine, nor-leucine salts or other derivatives or bound forms of Leucine with or without the addition of simple sugars, Amylopectin barley starch, ALA, maltodextrin, c rbohydrates or proteins can elicit an insulin spike that in tur causes the triggering of the mechanism to uplift carnitine into muscle as well as triggering the protein synthesis pathways necessary for healthy muscle.
- whey protein concentrate can elicit an insulin spike that in turn causes the triggering of the mechanism to uplift carnitine into skeletal, muscle as well as triggering protein synthesis pathways that are independent and/or synergistic with the pathways that are through insulin.
- Phenylalani e Phenylalanine AKG, Phenylalanine ethyl ester, N-acetyl- phenylalanine, salts or any other derivatives or bound forms of phenylalanine with or without the addition of simple sugars,
- Amylopectin barley starch, ALA, maltodext in, carbohydrates or proteins, e.g. whey protein concentrate can elicit an insulin spike that in turn causes the triggering of the mechanism to uplift carnitine (and) into muscle as well as triggering protein synthesis pathways that are independent and/or synergistic with the pathways that are through insulin. It is the case that Leucine and
- phenylalanine directly and indirectly also may have independent and synergistic effects on protein synthesis that utilize a different pathway than the insulin mediated pathway previously described and thus proving method and supplement for enhancing carnitine accum.ula.tion and. retention in humans and enhancing protein
- a low caloric supplement comprising reduced levels of carbohydrate and protein in combination with naturally occurring free amino acids is effective to amplify carnitine accumulation .
- This increased uptake and accumulation is similar to that observed with a high carbohydrate carnitine supplement.
- the low carbohydrate supplement advantageously reduces the quantity of carbohydrate consumed during carnitine supplementation, reducing the blood glucose level, and providing a more stable blood glucose level over time. Reducing the amount of carbohydrates consumed may also help to lose weight by reducing significantly the number of empty calories.
- the calorific content is calculated by the use of Atwater caloric conversion factors.
- the Atwater factors are based on the assumption that each gram of carbohydrate, protein and fat in the diet will yield 4, 4 and 9 calories (kcal) respectively.
- Those of skill in the art will also understand the term 'empty calories' to refer to foods that supply energy (calories) only, while other nutrients such as minerals, vitamins and proteins are missing or present in very low amounts.
- commercially available carnitine supplements proven to work typically comprise over 200 calories per gram of carnitine.
- the low carbohydrate carnitine supplement advantageously reduces the total number of calories for a serving of the supplement to increase total carnitine accumulation in skeletal muscle. Most preferably, a serving of the low
- carbohydrate supplement comprises less than 20 calories derived from carbohydrates, protein and naturally occurring free amino acids per gram of carnitine.
- carbohydrate preferabl refers to food carbohydrates such as simple carbohydrates and polysaccharides and combinations thereof; as well as derivatives thereof such as esters, and amides, as well as other derivatives, including derivatives that become active upon metabolism.
- Simple carbohydrates may refer to glucose, maltose, sucrose, galactose and lactose or combinations thereof.
- the simple carbohydrate is glucose and the
- polysaccharide is Vitargo ⁇ (see EP07 5096B1) .
- the carbohydrate is a combination of simple carbohydrate and polysaccharide the preferred ratio is 1 to 1
- a serving of the low carbohydrate supplement comprises 3g of carbohydrate per gram of carnitine.
- the most preferred protein is whey hydrolysate in the ratio of 6g to Ig of carnitine.
- a preferred non-dairy protein is soy protein.
- the most preferred naturally occur ing free; amino acids selected from the group of 20 naturally occurring free amino acids comprises 1.44q L-leucine and 1.44g L-Phenylalanine per gram of carnitine.
- Additional ingredients which increase carnitine accumulation in skeletal muscle may advantageously be added to the low carbohydrate supplement to further reduce the empty calories.
- additional additional ingredients may be added to the supplement.
- carbohydrate supplement it includes about. 20rng of alpha lipoic acid; 200mg of L-taurine; about 30meg of chromium; about 2g of 4- Hydroxyisoleucine; per gram of carnitine.
- the supplement may comprise small amounts of free fatty acids either for health benefits or for packaging. Most preferably the supplement comprises less than 3g of fat per serving.
- the present invention relates to a method of
- a low carbohydrate supplemental dietary composition that may activate increased levels of fatty oxidation as well as acti ating p otein synthesis machiner and deactivating catabolic processes and in so doing may reduce body fat; improve body
- compositions and assist in the treatment of muscle and obesity related illnesses or conditions as well as suppressing the effects of sarcopenia in the aging population and provide a range of well documented beneficial cardio-vascular and neuro cognitive effects.
- Vegetarians will specifically benefit from this invention by ensuring a stabilised supply of carnitine into key body organs such as the heart, kidney tissue and liver.
- a low carbohydrate carnitine with creatine supplement comprising a carnitine source, a protein source, a carbohydrate source and one or more naturally occurring free amino acids wherein a serving of the low carboh drate carnitine/creatine supplement is effective in amplifying carnitine and creatine accumulation in skeletal muscle.
- Also provided in accordance with the present invention is a serving of the low carbohydrate carnitine/creatine supplement comprising less than about 20 calories derived from the carbohydrate source, the protein source and naturally occurring free amd.no acids (per gram of carnitine/creatine) selected from the group consisting of L- Leucine and L ⁇ Phenylalanine .
- Also provided in accordance with the present invention is a method for manufacturing a low carbohydrate carnitine/creatine supplement comprising the step of mixing a carnitine and creatine source, a carbohydrate source, a protein sou ce and a naturally occurring f ee amino acid, blending and mixing for 30 minutes; and checking for uniformity/homogeneity and then aliquoting into a serving.
- the present invention provides a method for activating the protein synthesis machinery and deactivating catabolic processes within skeletal muscle by regulating molecular signals to control anabolic and anti-catabolic activity in skeletal muscle via nutrients including but not limited to amino acids and growth factors.
- the present invention may provide, by the consumption of a supplemental dieta y composition as set forth herein, a method, for improving body composition, treating muscle wasting or degenerative disease, suppressing the effects of sarcopenia in the aging population and/or providing a beneficial effect by influencing the genetic control system for global, protein synthesis.
- the present invention also provides a. composition and. methods to increase the level of fat oxidation in humans and in accordance with the present invention will enable dietary
- the present invention also provides for a method of supplementing the diet of an animal, comprising administering to the animal a serving of a low carbohydrate carnitine and creatine supplement comprising carnitine, creatine, carbohydrate, protein and one or more naturally occurring free amino acids .
- the present invention also provides a supplemental dietary
- composition that may include L ⁇ Leucine, including salts or
- the supplemental dietary composition may also include one or more of Amylopectin barley starch, dextrose, alpha-lipoic acid ( "ALA” ) , maltodextrin, WPC-80, bitter blocker flavours, citric acid, more flavour, potassium citrate, and sucralose.
- ALA alpha-lipoic acid
- WPC-80 bitter blocker flavours, citric acid, more flavour, potassium citrate, and sucralose.
- supplemental dietary composition may activate the protein synthesis machinery and deactivate catabolic processes within skeletal muscle by regulating molecular signals to control anabolic and anti- catabolic activity in skeletal muscle.
- the supplemental dietary composition may stimulate fatty oxidation, decrease muscle cata olism and improve body composition, treat muscle wasting or degenerative disease, suppress the effects of sarcopenia in the aging population and/or provide a beneficial effect by influencing the genetic control system for global protein synthesis.
- the present invention provides a low carbohydrate carnitine and creatine supplement comprising: carnitine, creatine, carbohydrate, protein and naturally occurring free amino acids wherein a serving of the supplement is effective in increasing carnitine and creatine accumulation in skeletal muscle.
- the present invention also provides for a method of increasing carnitine and creatine accumulation in skeletal muscle of an animal comprising the steps of: administering a low carbohydrate carnitine, creatine supplement comprising a serving of carnitine, creatine, carbohydrate, protein and one more naturally occurring free amino acids; and increasing the total muscle carnitine and creatine in the skeletal muscle of an animal .
- the present invention relates to a method, of
- a supplemental dietary composition may activate the protein synthesis machinery and deactivate catabolic processes within skeletal muscle by regulating molecular signals to control anabolic and anti-catabolic activity in skeletal muscle, and in doing so, may stimulate fatty oxidation, decrease muscle catabolism, treat, muscle wasting or degenerative disease, suppress the effects of sarcopenia in the aging population and/or provide a beneficial effect by influencing the genetic control, system for global protein s nthesis .
- the method of manufacturing a supplemental dietary composition includes the step of mixing one or more of L- Leucine, including salts or derivatives thereof, L-phenylalanine, including salts or derivatives thereof, carnitine including salts or derivatives thereof and creatine, including salts or derivatives thereof.
- the method of manufacturing a supplemental dietary composition may also include the step of mixing one or more of Amylopectin barley starch, dextrose, ALA, rnaltodextrin, WPC-80, bitter blocker flavor, citric acid, another flavor, potassium cit ate, sucralose and colouring.
- the present invention also provides for a method for manufacturing a low carbohydrate carnitine and creatine supplement comprising:
- carnitine creatine, carbohydrate, protein and. a naturally occurring free amino acid
- the method comprising the following steps: premixing micro-crystalline cellulose with the following ingredients to the premix: carnitine, creatine, Amylopectin barley starch, dextrose, high quality milk proteins, L-Phenylanine, L-Leucine, and
- microcrystalline cellulose adding magnesium stearate and silica which had been pre-sifted; blending and mixing for 20 minutes; and checking for unifo mity/homogeneity and then aliquot ing i to a serving .
- leucine and phenylalanine produce an anabolic signal in combination with the above-described benefits of carnitine and creatine supplementation is believed to have an additive effect on changing body composition e.g. weight loss and athleticism by the addition of lean mass and reduction of fat mass.
- Leucine, Leucine AKG, Leucine ethyl, ester, N-acetyl-leucine, nor-leucine salts or other derivatives or bound forms of Leucine with or without the addition of simple sugars, Amylopectin barley starch, ALA, maltodextrin, carbohydrates or proteins can elicit an insulin spike that in turn causes the triggering of the mechanism to uplift carnitine and creatine into muscle as well as triggering the protein synthesis pathways necessary for healthy muscle.
- Leucine, Leucine AKG, Leucine ethyl ester, N-acetyl-leucine, nor- leucine salts or other derivatives or bound forms of Leucine with or without the addition of simple sugars, amylopectin barley starch, ALA, maltodextrin, carbohydrates or proteins, e.g. whey protein concentrate can elicit an insulin spike that in turn causes the triggering of the mechanism to uplift carnitine and creatine into muscle as well as triggering protein synthesis pathways that are independent and/or synergistic with the pathways that are through insulin.
- Phenylalanine Phenylalanine AKG, Phenylalanine ethyl ester, N-acetyl-phenylalanine, salts or any other derivatives or bound forms of phenylalanine with or without the addition of simple sugars, Amylopectin barley starch, ALA, maltodextrin, carbohydrates or proteins, e.g. whey protein concentrate can elicit an insulin spike that in turn causes the triggering of the mechanism to uplift carnitine (and creatine) into muscle as well as triggering protein synthesis pathways that are independent and/or synergistic with the pathways that are through insulin.
- Leucine and phenylalanine directly and indirectly also may have independent and synergistic effects on protein synthesis that utilize a different pathway than the insulin mediated pathway previously described and thus proving method and supplement for enhancing carnitine/creatine accumulation/retention in humans and enhancing protein synthesis.
- the ingestion of a low carbohydrate carnitine with creatine supplement comprising reduced levels of carbohydrate and protein in combination with naturally occurring free amino acids is effective to amplify ei her or both carnitine and creatine accumulation.
- This increased uptake and accumulation is similar to that observed with a high carbohydrate carnitine/ creatine supplement.
- the low carbohydrate supplement advantageously reduces the quantity of carbohydrate consumed during carnitine/creatine supplementation, reducing the blood glucose level and providing a more stable blood glucose level over time. Reducing the amount of carbohydrates consumed may also help to avoid weight gain by reducing significantly the number of empt calories .
- the calorific content is calculated by the use of
- At ater caloric conversion factors The Atwater factors are based on the assumption that each gram of carbohydrate, protein and fat in the diet will yield 4, 4 and 9 calories (kcal) respectively.
- ⁇ 'empty calories' to refer to foods that supply energy (calories) only, while other nutrients such as minerals, vitamins and proteins are missing or present in very low amounts.
- carnitine and creatine supplements typically comprise over 200 calories per gram of carnitine and about 75 calories per gram of creatine.
- the low carbohydrate carnitine and/or creatine supplement advantageously reduces the total number of calories for a serving of the supplement to increase total carnitine and creatine accumulation in skeletal muscle.
- a serving of the low carbohydrate carnitine and/or creatine supplement advantageously reduces the total number of calories for a serving of the supplement to increase total carnitine and creatine accumulation in skeletal muscle.
- carbohydrate supplement comprises less than 30 calories derived from carbohydrates, protein and. naturally occurring free amino acids per gram of carnitine and creatine.
- carbohydrate preferably refers to food carbohydrates such as simple carbohydrates and polysaccharides and combinations thereof; as well as derivatives thereof such as esters, and amides, as well as other derivatives, including derivatives that become active upon metabolism.
- Simple carbohydrates may refer to glucose, maltose, sucrose, galactose and lactose or combinations thereof.
- the simple carbohydrate is glucose and the polysaccharide is Vitargo®.
- the carbohydrate is a combination of simple carbohydrate and polysaccharide the preferred ratio is 1 to 1,
- a. serving of the low carbohydrate supplement comprises 3g of carbohydrate per gram of carnitine/creatine .
- the most preferred, protein is whey hydrolysate in the ratio of 5g to Ig of carnitine and creatine,
- a preferred non- dairy protein is soy protein.
- the most preferred naturally occurring free amino acids selected from the group of 20 comprises 1.44g L-leucine and 1.44g L- Phenylalanine per gram of carnitine/creatine.
- Additional ingredients which increase carnitine and creatine accumulation in skeletal muscle may advantageously be added to the low carbohydrate supplement to further reduce the empty calories.
- additional ingredients may be added to the supplement.
- carbohydrate supplement includes about 20mg of alpha lipoic acid; 200mg of L-taurine; about 30meg of chromium; about 2g of 4- Hydroxyisoleucine; pe gram of carnitine/creatine and less than 3g of fat per serving.
- CoBiizyirte A enhstnceitteni co tpos it ions snd the
- CoASH coenzyme A
- Also provided in accordance; with the present invention is a course of servings of the exogenous precursers of CoASH synthesis derived from D-pantothenic acid and L-cysteine that is effective in increasing muscle tissue free CoASH concentration, increasing" muscle endurance performance, lowering muscle fatigue and lowering the heart rate during or without exercise.
- a dietary composition comprising a carnitine or creatine source, a protein source, a carbohydrate source, one or more naturally occurring free amino acids from the group leucine and phenylalanine and exogenous precursers of CoASH synthesis, D-pantothenic acid and L-cysteine wherein a course of the servings is effective in amplifying carnitine or creatine accumulation in skeletal muscle and increases the muscle tissue free CoASH concentration.
- compositions for improving muscle performance during exercise comprising at least two precursors of coenzyme A synthesis.
- a method of improving muscle performance during exercise by increasing the coenzyme A pool within the muscle by supplementing the muscle with at least two precursors of coenzyme A synthesis.
- a method of improving endurance exercise performance of muscle comprising the supplementing the coenzyme A pool within the muscle by administering at least two precursors of
- Coenzyme A synthesis Preferably one of the precursors is D-pantothenic acid or a functionally equivalent derivative thereof.
- the other precursor is L-cysteine or a functionally equivalent derivative thereof.
- the precursors are provided in a composition which may be administered directly to the muscle tissue, or alternatively to a body comprising the muscle, such as by way of ingestion and/or injection.
- the composition may be in the form of a food or dietary supplement and may be solid, e.g. powder, tablet , capsule or caplet or may be liquid.
- L-cysteine or a functionally equivalent derivative thereof is provided in an amount in the range 0.05g to 5q, and.
- the precursors may be administered daily in the aforesaid amounts, over a period of several days.
- the precursors may be administered over a period of between five and seven days and preferably five days or alternatively they may be cidministered continuously over longer periods .
- Preferably the precursors are provided simultaneously.
- a substance comprising pantothenic acid and Cysteine or functionally equivalent derivatives thereof, for use in the manufacture of a medicament, for the treatment of muscle to improve endurance exercise fatigue.
- a substance comprising pantothenic acid and Cysteine or f nctionally equivalent de ivatives thereof, for use in the manufacture of a medicament for the treatment of muscle fatigue,
- a substance comprising pantothenic acid and cysteine or functionally equivalent derivatives thereof, for use in the manufacture of a medicament for lowering the heart rate.
- the present invention provides a substance comprising pantothenic acid and cysteine or functionally equivalent derivatives thereof, a low carbohydrate carnitine and creatine supplement comprising: carnitine, creatine, carbohydrate, protein and naturally occurring free amino acids (specifically Leucine and phenylalanine) wherein a serving of the supplement is effective in increasing carnitine and creatine accumulation in skeletal muscle to combine a number of skeletal muscle benefits including but not exclusively fat loss, the preservation of lean muscle mass, a reduction in the heart rate and muscle fatigue and an increase in muscle endurance capacit .
- a low carbohydrate carnitine and creatine supplement comprising: carnitine, creatine, carbohydrate, protein and naturally occurring free amino acids (specifically Leucine and phenylalanine) wherein a serving of the supplement is effective in increasing carnitine and creatine accumulation in skeletal muscle to combine a number of skeletal muscle benefits including but not exclusively fat loss, the preservation of lean muscle mass, a reduction in the heart rate and
- CoASH Coenzyme A
- the cellular CoASH pool is limited ⁇ -45-50 ⁇ /kg dry tissue, of which 95% is located within the mitochondria), and during conditions of increased energy demand, its concentration could be markedly reduced thereby limiting the rate of carbohydrate and/or fat oxidation.
- the fuel that skeletal muscle uses during exercise depends upon the intensity and duration of the exercise to which the rnuscle is exposed. Low intensity exercise, i.e. exercise using less than half of the physical abilities of the muscle, uses fat as the predominant fuel and therefore fat oxidation is the primary metabolic reaction fueling the muscle. Fat reserves, particularly in the human body, are generally quite large such that the availability of fat as a fuel is unlikely to limit the performance at such low intensity 1eve;Is.
- the amount of exercise that the muscle can perform is generally restricted by the level of muscle glycogen reserves . It has been established in accordance with the present invention, that increasing the muscle cellular coenzyme A (CoASH) pool reduces the competition between carbohydrate and fat oxidation in skeletal muscle tissue, resulting in an improvement in fuel oxidation and importantly enabling the muscle to continue exercising beyond the 'natural' exhaustion point.
- CoASH muscle cellular coenzyme A
- the invention may also help in the treatment of muscle disorders that impair muscle performance and may help in alleviating muscle fatigue. This could have very many advantages and uses particularly for people or animals required to undertake prolonged work or exercise or who are required to partake in exercise in conditions where food supplies may be intermittently available or otherwise limited.
- the muscle tissue free CoASH concentration or pool is increased in accordance with the p esent invention by providing exogenous precursors of CoASH synthesis, D ⁇ pantothenic acid and L ⁇ -cysteine.
- the D ⁇ pantothenic acid and/or L-cysteine may be replaced by functionally equivalent derivatives thereof.
- the D-pantothenic acid and L-cysteine or functionally equivalent derivatives may be provided in a composition for oral administration to a body comprising the muscle, or may be provided in any other suitable form, e.g. solid or liquid, for alternative administration to the body comprising the muscle tissue, or directly to the muscle tissue itself .
- the D-pantothenic acid may, in some cases, be provided in an amount within the range O.OSgms to 5gms.
- the L-cysteine may, in some cases, be provided in an amount within the range O.OSgms to 5gms .
- the precursors may be administered over a period of several days for example 5-7days.
- the precursors may be administered continuously over longer pe iods.
- the precursors are preferably administered simultaneously, although it is within the scope of the present invention for them to be administered separately, e.g. sequentially.
- Example 1 Supplementation with CoA precursors im ro es exercise performance
- V02max V02max .
- Carnitine group also demonstrated a 10% increase in work output from baseline in the performance trial (343 ⁇ 20.0 vs 310 ⁇ 26.8 KJ, respectively, P ⁇ 0.01) , whilst work output was unchanged in control.
- Volunteers 7 healthy male volunteers. All volunteers were medically screened and eligible to participate.
- Protocol The volunteers were required to attend the lab for 3 trials. Each consisted of a morning and an afternoon attendance each lasting for approximately 4 hours. Volunteers were required to rest on a bed. A baseline blood sample was taken. Each trial was administered via a nasogastric tube over an approximate time of 7 minutes. After a 3 hour protocol a second trial solution was administered. A third solution was administered in the following morning trial. Each trial was separated by 12 days.
- Blood sampling Blood samples were collected for 3 hours after administration of the solution. Eleven blood samples were obtained at 15 minute intervals during the first hour then increasing to 20 minutes for the next, two hours. Approximately 3ml of blood was transferred to a lithium heparin containing tube and a further 3ml was allowed to clot, for plasma, and insulin analysis. It is now known that, insulin promotes muscle carnitine accumulation in healthy young volunteers but required a high physiological insulin concentration to be maintained to achieve this effect.
- the multiple studies referred to are also cross referenced into (i) stud work concerning the activation of genes encoding proteins that regulate muscle fat oxidation from a pre -determined cohort of 170 genes known to regulate muscle fat and carbohydrate; oxidation and; (ii) , aetiology of intra-muscular lipid (ILM) accumulation and muscle insulin resistance in older age groups to determine if this proposed low caloric method can dampen negative age related responses.
- the objective of the direction of the studies noted is to produce a range of diverse market formulations for categories such as diet and weight loss and expanding into clinical markets associated with conditions such as type 2 diabetes and other obesity linked conditions .
- the protocol for each of these visits is depicted in Figure 1.
- pantothenic acid dose is eliminated from the body within 5 days
- pantothenic acid supplementation was employed in an attempt to drive CoASH formation and cysteine ingestion simply to be sure no deficiency existed.
- CoASH Coenzyme A
- acyl-CoA synthetase ⁇ ACS As a substrate for the enzyme acyl-CoA synthetase ⁇ ACS, CoASH allows the activation of cytosolic fatty acids to fatty acyl-CoAs before their subsequent delivery to the mitochondria via the carnitine shuttle system.
- mitochondrial CoASH is required for the carnitine palmitoyltransferase 2 (CPT2) -mediated transesterification of acylcarni tine to carnitine and acyl-CoA.
- CPT2 carnitine palmitoyltransferase 2
- the aim of the study therefore was to elevate the muscle free CoASH pool in healthy humans via 7 days of oral supplementation with pantothenic acid and cysteine ⁇ precursors of endogenous CoASH biosynthesis) in order to further elucidate the role of CoASH availability in the regulation of muscle fuel metabolism during exercise.
- 1 wk of dietary fat 1 wk of dietary fat
- pantothenic acid supplementation (1.5 g/day) has previously been shown to reduce blood lactate concentration compared with control during steady-state exercise at 75% Vo2i MX however, the underlying mechanism within skeletal muscle was not investigated. Finally, it was hypothesized that if pantothenic acid and cysteine
- ingestion of whey protein is an effective insulin secretagogue .
- Hydrolysis of whey protein prior to ingestion augments the maximal insulin concentration by a mechanism that is unrelated to gastric emptying of the peptide solution.
- EAA essential amino acids
- the milk protein, whey is a rich source of EAAs . Addition of whey protein to a carbohydrate drink enhances the insulin response to that attained by ingestion of carbohydrate alone (Van Loon et al., 2000).
- the aim of this study was to determine the insulinotropic response following ingestion of native and hydrolysed whey protein and to evaluate whether a difference exists in two of the primary
- regulators of this response i.e. the rate of gastric emptying (GE) and. the ci culati g concentration of amino acid of known
- SPSS SPSS Inc, Chicago, IL
- Body mass and whole-body fat mass increased over 12 weeks in Control by 1.9 and 1.8 kg, respectively but did not change In technology group (see Figure 4).
- a novel finding of the study was that this prevention of fat gain was associated with a greater energy expenditure and fat oxidation during low-intensity physical activity, and an adaptive increase in expression of gene networks involved in muscle insulin signalling and fatty acid metabolism.
- compositions of the present, invention nullifies the effect of additional/excess calories consumed to achieve a "zero calorie" effect. This has clear benefits in the context of dieting, well- being, as well as in the treatment of obesity and obesity-related conditions. Moreover, the improved body composition, in particular fat loss or prevention of fat gain, is beneficial in the context of athletic performance and training.
- Arenas J. , Ricoy, J.R. , Encinas, A.R., Pola, P., D'Iddio, S.,
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Abstract
Dietary compositions comprising a carnitine source, a protein source, a carbohydrate source one or more free amino acids, including L-leucine and/or L-phenylalanine, use of said compositions in promoting healthy body composition, including prophylactic or therapeutic treatment of medical conditions.
Description
Digfcg^y Cor^osit^
Field of the Invention
The present invention relates to dietary compositions and their use in improving body composition, e.g. reducing body fat and/or increasing lean mass, improving health and treating certain conditions .
The body's carnitine; store is found almost exclusively in skeletal muscle, where it plays an essential role in the transport of fat into the body's mitochondria so it can then be used for energy production. The muscle total carnitine pool is about 25 mmol/kg dry muscle, and is known to be vital in dictating the proportions of fat and carbohydrate used by muscle for energy production during exercise and at high exercise intensities, the availability of free carnitine limits fat oxidation for energy production. However, we now know that increasing skeletal, muscle free carnitine through supplementation prevents the build-up of lactic accumulation in muscle delaying the onset of muscle fatigue, increases fat oxidation at nil/low to medium intensity exercise and increases the
availability of carbohydrate for muscle energy production during high intensi t exercise . Despite considerable: claims to the contrary, it has been
unequivocally proven that neither oral nor intravenous L-carnitine administration by itself increases skeletal muscle carnitine content by a measurable amount in humans with normal muscle carnitine content. This is because carnitine is transported into skeletal muscle against a considerable concentration gradient, such that blood carnitine availability, (even in the non-carni tine
supplemented state) , can limit muscle carnitine transport and storage. For example, feeding 2 g/day of L-carnitine for 3 or 6 months or administering a 30 rag/kg body mass intravenous L-carnitine bolus failed to increase muscle carnitine content or improve exercise capacity in healthy human subjects. Furthermore, studies that have reported positive effects of L-carnitine supplementation
on muscle metabolism have simply not. measured muscle carnitine content, leading to questions being raised regarding the validity of the findings. It is clear therefore that if an increase in muscle carnitine content is to be achieved, then an alternative strategy to simply ingesting L-carnitine on its own is required.
Like carnitine, the body's store of creatine is found in muscle, where it plays a fundamental role in maintaining energy production during exercise. The total creatine store (phosphocreatine and free creatine) in healthy, non-vegetarian, subjects is about 124 mmol/kq dry muscle, but it can vary widely between individuals (100-150 mmol/kg dry muscle) . Dietary creatine supplementation at a. rate of 20g er day for 5 days has been shown to increase muscle total creatine content on average by 20%. A similar, but more gradual, increase is obtained when creatine is ingested at a rate of 2 to 5g per day for about a month.
It is widely accepted that elevating the muscle total creatine store can enhance performance during high-intensity exercise and therefore creatine supplementation has become enormously popular in athletes wishing to improve athletic performance in snort duration, very high intensity sports. It is also possible that creatine supplementation may be of therapeutic benefit to patients wi h muscular and neurological disorders.
Research tells us that the metabolic and physiological effects of creatine supplementation are positively related to the extent of muscle creatine accumulation during supplementation. Therefore to exert, an optimal effect on performance and metabolism, it is necessary to increase the muscle total creatine content by about 20 mmol/kg dry muscle or more {as described above). The variations between individuals in creatine accumulation during supplementation can be partly accounted for by differences in pre-supplementation muscle creatine concentrations, and muscle fibre type distribution, however, creatine related research is ongoing and may in time reveal, more. See Greenhaff et al . (1994) supra & Casey et al. (1996) AM J Physiol: 271 (1) :E31-7.
Subsequently it has been demonstrated that a supplement comprising a 1:1 ratio of carbohydrate and milk protein (in required amounts) produces the same whole body creatine retention as a supplement comprising 100% carbohydrate. See Steenge et al . (2000) J Appl Physiol: 1165-71. The increase in creatine accumulation is believed to result from insulin stimulated creatine transport.
It is widely accepted that muscle performance during exercise is naturally regulated by the metabolic reactions primarily involved in fat and carbohydrate oxidation within the muscle tissue.
Exercise intensity and duration are two major factors that affect whether muscle uses carbohydrate and/or fat during exercise to cover the energy costs of that exercise. As exercise intensity increases and the duration decreases? the predominant fuel becomes carbohydrate. Conversely, as exercise intensity decreases and the duration increases, the predominant fuel becomes fat. The maximal competition between these two main energetic substrates to enter oxidative pathways seems to occur at -75% of maximal oxygen consumption (V02mil) .
During exercise at low intensity i.e. less than half of the muscle's the predominant fuel is fat. Since the human body has relatively large reserves of fat it is unlikely that fat availability would limit the performance at such work levels. As exercise intensity increases and carbohydrate becomes the predominant fuel the human body's limited carbohydrate stores (mainly in the form of glycogen) causes the duration of the physical effort at intensities between 60-85% of our VO^x to decline correspondingly and the exhaustion time usually matches the point at which muscle glycogen reserves are depleted .
Maintenance of exercise performance; during prolonged endurance tasks is key to the successful completion of those tasks. Dietary
strategies for maximizing the availability of stored carbohydrate are well established but, higher intensity exercise (about 75% of a
person's V02,„M) cannot be sustained for more that approximately 90 minutes in most people and is accompanied by a progressive depletion of some of the metabolic intermediates in the active muscles. There remains a need to provide dietary compositions for activating fatty oxida ion, improving body composition, muscular strength and delaying the onset of muscle fatigue. The present invention addresses these and other needs. Summary of the Invention
Broadly, the present invention provides products and methods for activating fatty oxidation in skeletal muscle, inter alia, by enhancing uptake by muscle of carnitine and/or creatine, and/or increasing the cellular coenzyme A (CoASH) pool. The present inventor has surprisingly found that a low carbohydrate (and therefore potentially low calorie) composition incorporating specific free amino acids, such as L-leucine and L-phenylalanine, provide enhanced carnitine uptake by skeletal muscle. Accordingly, in one aspect the present invention provides a dietary composition comprising: a carnitine source; a carbohydrate source; a protein source; and one or more free amino acids.
In some cases in accordance with the invention said one or more free amino acids comprise:: {i) L-leucine or a salt or derivative: thereof; and/or (ii) L-phenylalanine or a salt or derivative thereof.
The present invention provides, in one aspect, a dietary composition compri sing :
(i) a carnitine source; and
(ii) (a) free L-leucine, or a salt or amino acid derivative thereof, and/or
(b) free L-phenylalanine, or a salt or amino acid, deri ati e thereof.
The free L-leucine or salt or amino acid derivative thereof may, for example, be selected from the group consisting of: L-leucine,
leucine alpha ketoglutarate (AKG) , leucine ethyl ester, -acetyl- leucine and nor-leucine salt.
The free L-phenylalanine or salt or amino acid derivative thereof may, for example, be selected from the group consisting of: L- phen lala i e, phe ylalanine alpha ketogluta ate, phen lalanine ethyl ester and N-acetyl-phenylalanine .
In some cases in accordance with the present invention, the composition comprises both L-leucine and L-phenylalanine.
In some cases in accordance with the present invention, L-leucine is present in an amount within the range 0,1 to 9.0 g per g of carnitine, for example, within the range 0.2 to 7.5 g per g of carnitine or within the range 1 to 6 g per g of carnitine. In certain cases L-leucine is present at about. 1.44 g per g of carnitine .
In some cases in accordance with the present invention, L- phenylalanine is present in an amount within the range 0.1 to 9.0 g per g of carnitine, for example within the range 0.2 to 7.5 g per g of carnitine or within the range 1 to 6 g per g of carnitine. In certain cases L-phenylalanine is present at. about 1.44 g per g of carnitine .
It is contemplated herein, in accordance with the present invention, that one or more servings (for example a course of dietary
supplementation over a period of days or weeks) of the composition of the invention is effective to enhance carnitine accumulation in skeletal muscle, liver and/or kidney tissue in a mammalian subject. It. is particularly advantageous that, the presence of certain amino acids such as L-leucine and/or L-phenylalanine, stimulates an insulin-dependent carnitine uptake into muscle without the need for a sugar-induced insulin spike. This allows the muscle carnitine enhancement, to be achieved 'without requiring excessive carbohydrate supplementation and the unwanted e cess calorie load that such carbohydrate supplementation would entail. The non- reliance of the
compositions of the present, invention on sugar-induced insulin spike is especially advantageous in the context of individuals who exercise only moderately or not at all because excess carbohydrate may not be wanted. Conversely, as described in, e.g., Example 8 herein, the ability of the enhanced muscle carnitine levels to stimulate greater fatty acid oxidation mitigates a carbohydrate calorie load such that even when a composition of the present invention includes significant carbohydrate, the net effect of the composition may be "zero calorie" in terms of its effect on body fat.
In some cases in accordance with the present invention the dietary composition may further comprise creatine or a salt thereof. In some cases, creatine is present in an amount within the range 0.1 to 9.0 g per g of carnitine. In certain cases, creatine is present at about 1:1 ratio by weight, to carnitine.
In accordance with the present invention, one or more servings (for example a course of dietary supplementation over a period of days or weeks) of the composition of the invention may be effective to enhance creatine accumulation in skeletal muscle in a. mammalian sub ect .
In a second aspect the present invention provides a dietary composition comprising D-pantothenic acid and L-cysteine. The composition thereby provides coenzyme A (CoASH) precursors such that the CoASH pool within muscle: of a subject may be enhanced. In some; cases, D-pantothenic acid is present in an amount within the range 0.05 g to 5 g. In some cases, L~cysteine is present in an amount within the range 0.05 g to 5 g.
In accordance with this aspect of the present invention, one or more servings of the composition may be effective to enhance coenzyme A accumulation in muscle tissue in a mammalian subject .
Furthermore, the benefits of the fi st and second aspects of the present invention may be cidvantageousiy combined. Accordingly, the
present invention provides a dietary composition in accordance with the first aspect of the invention which further comprises D- pantothenic acid and L-cysteine. In some cases, D-pantothenic acid is present in an amount within the range 0.05 g to 5 g per g of carnitine. In some cases, L-cysteine is present in an amount within the range 0.05 g to 5 g.
Advantageously, one or more servings {for example a course of dietary supplementation over a period of days or weeks) of the composition of the first aspect of the present invention may be effective to enhance both coenzyme A accumulation and carnitine accumulation, and. in certain cases creatine accumulation, in muscle tissue in a mammalian subject. In accordance with any aspect of the present invention, the dietary composition may further comprise at least, one carbohydrate. In some cases, the at least one carbohydrate comprises a polysaccharide such as Vitargo®. In some cases, the at. least one carbohydrate comprises a carbohydrate selected from the group consisting of: glucose, maltose, sucrose, galactose and. lactose. In certain cases, the amount of carbohydrate may be within the range 0.1 to 9.0 g per g of carnitine. In some cases, the dietary composition in accordance with any aspect of the present invention is provided in the form of a low carbohydrate serving having not more than 3 g carbohydrate per g of carnitine.
In accordance with any aspect of the present invention, the dietary composition may further comprise at least one protein. In some cases the amount of protein is in the range 0.1 to 9.0 g per g of carnitine, for example, in the range 0.2 to 7.5 g per g of carnitine or in the range 1 to 6 g per g of carnitine.
In some cases the dietary composition in accordance with any aspect of the present invention comprises whey protein, for example, whey protein hydrolysate ( PH) , Additionally or alternatively, the dietary composition may comprise soy protein.
In accordance with any aspect of the present invention, the dietary composition may be provided in the form of a serving having less than 30 calories derived from carbohydrates, protein and naturally occurring free amino acids per g of carnitine and, if present, creatine. Specifically contemplated herein are truly "low calorie" servings that avoid or minimise empty calories.
In accordance with any aspect of the present invention, the dietary composition may be provided in the form of a serving having not more than 3 g of fat.
In accordance with any aspect of the present invention, the dietary composition may further comprise one or more {such as two, three, four or five or more) of the following: amylopectin barley starch, alpha-lipoic acid ("ALA"), maltodextrin, dextrose, WPC-80, one or more flavourings, colouring, citric acid, potassium citrate, L~ taurine, chromium, 4-hydroxyisoleucine and sucralose. In certain cases, ALA is present at an amount in the range 1-100 mg or 5-50 mg per g of carnitine. In some particular cases, the composition comprises about 20 mg ALA, 200 mg L-taurine, 30 mg chromium and about 2 to 4 g 4-hydroxyisoleucine per g of carnitine.
In a third aspect, he p esent inve tion provides an article of manufacture comprising packaging housing a plurality of discrete servings of the dietary composition in accordance with any one of the first or second aspects of the invention and, optionally, a label or insert with instructions regarding dose and or frequency of said servings. In a fourth aspect, the present invention provides a food or drink product incorporating the dietary composition in accordance with any¬ one of the first or second aspects of the invention.
In a fifth aspect, the present invention provides a dietary
composition in accordance with any one of the first or second aspects of the invention for use in a method of medical treatment .
In a sixth aspect, the present invention provides a dietary composition in accordance with any one of the first or second aspects of the invention for use in a method of treatment of obesity, metabolic syndrome, muscle wasting, diabetes, sarcopenia, degenerative disease and/or muscle fatigue in a mammalian subject.
In a seventh aspect, the present invention provides a method of treatment of a mammalian subject having obesity, metabolic syndromes, muscle wasting, diabetes, sarcopenia, degenerative disease and/or muscle fatigue, said method comprising administering a dietary composition in accordance with any one of the first or second aspects of the invention to the mammalian subject in need thereof. in an eighth aspect, the present invention provides use of a dietary composition in accordance with any one of the first or second aspects of the invention in the supplementation of a vegetarian diet of a mammalian subject.
In a ninth aspect the present invention provides a method of enhancing athletic performance of a mammalian subject, comprising administration of one or more servings of the dietary composition in accordance with any one of the first or second aspects of the invention to the subject. In a tenth aspect, the present invention provides a method of reducing absolute body fat and/or relative body fat per unit of lean body mass, or of preventing gain in absolute or relative body fat, comprising administration of one or more servings of the dietary composition in accordance with any one of the first, or second aspects of the invention to the subject.
In accordance with any aspect of the present invention, the mammalian subject may be a human or a domestic, working or companion animal (e.g. a dog, cat, horse, including a race horse) .
Preferably, the subject is a human. A wide cross-section of human sub ects are specifically contemplated. For example, the subject may be an athlete, a vegetarian, an aged person (e.g. of greater
than 60 or 70 or 80 years of age) , an overweight or obese person (e.g. Body mass index (BMI) of >25, >30 or >35) . The human subject may be of generally good health or may be suffering from a condition selected from: obesity, metabolic syndrome, muscle wasting, diabetes, sarcopenia, degenerative disease and/or muscle fatigue.
In an eleventh aspect, the present invention provides a method for producing a dietary composition in accordance with any one of the first or second aspects of the invention, comprising:
providing a carnitine source and one or both of: (i) a source of leucine, or a salt or derivative thereof, and (ii) a source of phenylalanine, or a salt or derivative thereof;
mixing and/or blending the ingredients to uniformity; and optionally aliquoting the resulting dietary composition mixture into a plurality of servings .
The method in accordance with this aspect of the present invention may further comprise providing and mixing with the other ingredients one or more (such as two, three, four or five or more) of the following: creatine, D~pantothenic acid, L--cysteine, carbohydrate, vitargo®, glucose, protein, whey protein hydrolysate, soy protein, amylopectin barley starch, alpha-lipoic acid ( "ALA" ) , maltodextrin, dextrose, WPC-80, flavour, citric acid, potassium citrate,
colouring, L-taurine, chromium, 4-hydroxyi soleucine and sucralose.
In some cases, the method comprises the steps:
premixing microcrystalline cellulose with carnitine,
amylopectin barley starch, dextrose, high quality milk proteins, L-phenylalanine and L-leucine;
adding magnesium stearate and silica which have been pre- sifted;
blending and mixing for about 20 minutes ;
checking for uniformity/homogeneity; and
aliquoting into one or more servings .
In a twelfth aspect, the present invention provides a method for producing a food or drink product, comprising the step of
incorporating the dietary composition in accordance with any one of the first or second aspects of the invention into a food or drink mixture at a stage prior to the final packaging of the food or drink mixture to form the end food or drink product .
In some cases, the food or drink product is selected from the group consisting of: a soup, a pasta sauce, a cereal bar, a milkshake pre-- mix, a. breakfast cereal and a sports drink. Although the final food, or drink product may, in certain cases, include carbohydrate and/or fat at a level above; that contemplated for certain embodiments of the dietary composition of the present invention, it is envisaged that the fat burning effect of the carnitine enhancement achieved by the technology of the present invention mitigates or nullifies the potential fat gain that would otherviise be induced by excess consumption of calorie-rich ingredients of the final food or drink product, such as carbohydrate (the so-called "zero calorie" effect.) .
Embodiments of the present, invention will now be described by way of example and not limitation with reference to the accompanying figures. However various further aspects and embodiments of the present invention will be apparent to those skilled in the art in view of the present disclosure.
"and/or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example "A and/or B" is to be taken as specific
disclosure of each of (i) A, (ii) B and (iii) A and B, lus as if each is set out individually herein. The present invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or is stated to be expressly avoided. Section headings are used herein are for convenience only and are not. to be construed as limiting in any way.
Unless context dic ates otherwise, the descriptions and. definitions of the features set out herein are not limited to any particular
aspect or embodiment of the invention and apply equally to all aspects and embodiments which are described.
Brief Description of the Figures
Figure 1 shows the experimental protocol employed in the coenzyme A precursor supplementation studies. Cycling exercise at 75% V02max for approximately 90 mins . Is followed by a work output pe formance; test. Muscle samples were taken at the indicated time points (broad arrows; 0, 60 and 90 mins.); blood and expired gas samples were taken at the indicated time points (narrow arrows) .
Figure 2 shows a graph of heart rate (bpm) for pre-placebo (open circles), pre-supplementation {open squares), post-placebo (filled circles) and post-supplementation (filled squares), plotted against exercise time.
Figure 3 shows a graph of plasma insulin response plotted against time for subjects having taken whey protein (WPI; open triangles) or whey protein hydrolysate (WPH; filled squares) . The inset shows
Cmax (pmol/L) maximum insulin concentration for WPI (open bar) and WPH (filled bar) .
Figure 4 shows fat mass in kg for control subjects (left hand bars) at 0 and at 12 weeks of twice-daily carbohydrate supplementation
(trunk - filled bars; legs - hatched bars and arms - open bars) and test subjects {right hand bars) at 0 and 12 weeks of twice-daily carbohydrate + carnitine technology supplementation (trunk - filled bars; legs - hatched bars and arms - open bars). The control group exhibited a statistically significant gain in fat (see asterisk); the carnitine- supplemented group did not exhibit any significant fat gain. The carnitine-supplemented group displayed a higher starting fat mass (at. 0 weeks) than the control group, but. this was not a statistica11y significan.t. di fference.
Detailed Description
Ga nifcins snh&ncemenfc compositions and their
In accordance the present invention there is provided a low caloric supplement comprising a carnitine source, a protein source, a carbohydrate source and one or more naturally occurring free amino acids wherein a serving of the low carbohydrate carnitine./ creatine supplement is effective in amplifying carnitine accumulation in skeletal muscle, liver and/or kidney tissue.
Also provided in accordance with the present invention is a serving of a low caloric supplement as defined herein wherein the supplement has no more than about 30 calories derived from a carbohydrate source, the supplement further comprising: a protein source; a carnitine source; and naturally occurring free amino acids (in specific amounts per gram of carnitine) selected from the group consisting of L-Leucine and L-Phenylalanine .
Also provided in accordance with the present invention is a method for manufacturing a low caloric supplement, comprising the step of mixing a carnitine source, a carbohydrate source, a protein source and. a naturally occurring free amino acid, blending and mixing for 20 minutes; and checking for uniformity/homogeneity and. then aliquoting into a serving.
Dietary supplements to be manufactured and methodologies employed, as defined herein, find, use; in the treatment of conditions of the human or animal body associated with a need to reduce excess body fat including conditions associated with an impairment of fat oxidation, obesity or type 2 diabetes or to assist in energy restriction dietary regimes that focus on the reduction of body fat. In addition, the present invention may in some cases enable dietary supplements for vegetarians who are now known to have reduced skeletal carnitine transport capacity compared to non-vegetarians specifically for improving the health of vital organs such as heart, kidney and liver in humans.
The present invention also provides feu: a method of supplementing the diet of an animal, comprising administering to the animal a
serving of a low caloric supplement comprising carnitine,
carbohydrate, protein and one or more naturally occurring free amino acids . The present invention also provides a supplemental dietary
composition that may include L-Leucine, including salts or
derivatives thereof, L-phenylalanine, including salts or derivatives thereof, carnitine and/or, including salts or derivatives thereof, and may also include sources of dietary protein and/or
carbohydrates. 'The supplemental dietary composition may also include one or more of Amylopectin barley starch, dextrose, alpha-lipoic acidC'ALA"), maltodextrin, WPC-80, bitter blocker flavours, citric acid, more flavour, potassium citrate, and sucralose. The
supplemental dietary composition may activate the protein synthesis machinery and deactivate catabolic processes within skeletal muscle by regulating molecular signals to control anabolic and anti- catabolic activity in skeletal muscle. In doing so the supplemental dietary composition may stimulate fatty oxidation, decrease muscle catabolism and improve body composition, treat muscle wasting or degenerative disease, suppress the effects of sarcopenia in the aging population a d/or provide a beneficial effect by influenci g the genetic control system for global protein synthesis.
In addition, the present invention provides a low caloric supplement comprising; ca nitine, carbohydrate, protein and naturally occur ing free amino acids wherein a serving of the supplement is effective in increasing carnitine accumulation in skeletal muscle.
The present invention also provides for a method of increasing carnitine accumulation in skeletal muscle of an animal comprising the steps of: administering a low carbohydrate carnitine supplement comprising a serving of carnitine, carbohydrate, protein and one more naturally occurring free amino acids; and increasing the total muscle carnitine in the skeletal muscle of an animal.
In addition, the present invention relates to a method of
manufacturing a low caloric supplemental dietary composition that
may activate the protein, synthesis machinery and deactivate catabolic processes within skeletal muscle by regulating molecular signals to control anabolic and anti-catabol ic activity in skeletal muscle, and/or provide a beneficial effect by influencing the genetic control system for global protein synthesis and may also stimulate fatty oxidation, decrease muscle catabolism, treat muscle wasting or degenerative disease, suppress the effects of sarcopenia i he aging population, and improve vital organ health in
vegetarians ,
In certain cases, the method of manufacturing a supplemental dietary composition includes the step of mixing one or more of L-Leucine, including salts or derivatives thereof, L-phenylalanine, including salts or derivatives thereof and carnitine including salts or derivatives thereof.
The method of manufactureng a supplemental dietary composition may also include the step of mixing one or more of Amylopectin barley starch, dextrose, ALA, maltodextrin, WPC-80, bitter blocker flavour, citric acid, another flavour, potassium citrate, sucralose and colou ing.
The present invention also provides for a method for manufacturing a low caloric supplement comprising; carnitine, carbohydrate, protein and a naturally occurring free amino acid the method comprising the following steps: premixing microcrystalline cellulose with the following ingredients to the premix; carnitine, Amylopectin barley starch, dextrose, high quality milk proteins, L-Phenylalanine , L~ Leucine, and microcrystalline cellulose; adding magnesium stearate and silica which had been pre-sifted; blending and mixing for 20 minutes; and checking for uniformity/homogeneity and then aliquoting into a serving.
Recent research has demonstrated that key amino acids, e.g. Leucine and phenylalanine play an important role as nutrient signals involved in insuli production via key components as set forth in the present invention, in conjunction with the direct signalling
effect of critical amino acids as set forth in the present invention more specifically Leucine and phenylalanine produce an anabolic signal in combination with the known benefits of carnitine
supplementation is believed to have an additive effect on changing body composition e.g. weight loss and athleticism by the addition of lean mass and reduction of fat mass.
More specifically, using Leucine, Leucine alpha ketoglutarate (AKG) , Leucine ethyl ester, N-acetyl --leucine, nor-leucine salts or other derivatives or bound forms of Leucine with or without the addition of simple sugars, Amylopectin barley starch, ALA, maltodextrin, c rbohydrates or proteins can elicit an insulin spike that in tur causes the triggering of the mechanism to uplift carnitine into muscle as well as triggering the protein synthesis pathways necessary for healthy muscle. Using Leucine, Leucine AKG, Leucine ethyl ester, ^-acetyl-leucine, nor-leucine salts or other
derivatives or bound forms of Leucine with or without the addition of simple sugars, Amylopectin barley starch, ALA, maltodextrin, carbohydrates or proteins, e.g. whey protein concentrate can elicit an insulin spike that in turn causes the triggering of the mechanism to uplift carnitine into skeletal, muscle as well as triggering protein synthesis pathways that are independent and/or synergistic with the pathways that are through insulin. Using Phenylalani e, Phenylalanine AKG, Phenylalanine ethyl ester, N-acetyl- phenylalanine, salts or any other derivatives or bound forms of phenylalanine with or without the addition of simple sugars,
Amylopectin barley starch, ALA, maltodext in, carbohydrates or proteins, e.g. whey protein concentrate can elicit an insulin spike that in turn causes the triggering of the mechanism to uplift carnitine (and) into muscle as well as triggering protein synthesis pathways that are independent and/or synergistic with the pathways that are through insulin. It is the case that Leucine and
phenylalanine directly and indirectly, also may have independent and synergistic effects on protein synthesis that utilize a different pathway than the insulin mediated pathway previously described and thus proving method and supplement for enhancing carnitine
accum.ula.tion and. retention in humans and enhancing protein
synthesis .
The ingestion of a high carbohydrate carnitine supplement has been shown to result in an increase in total muscle carnitine uptake and accumulation as compared wi h the intake of carnitine alone;. It is believed that the carbohydrates increase carnitine uptake by stimulating secretion of insulin. The resulting increase in plasma insulin increases the activity of a sodium-dependent muscle carnitine transporter. This is supported by evidence that insulin augments muscle carnitine accumulation when present at a
coneentration >100mU/ 1.
It has been unexpectedly found that the ingestion of a low caloric supplement comprising reduced levels of carbohydrate and protein in combination with naturally occurring free amino acids is effective to amplify carnitine accumulation . This increased uptake and accumulation is similar to that observed with a high carbohydrate carnitine supplement. The low carbohydrate supplement advantageously reduces the quantity of carbohydrate consumed during carnitine supplementation, reducing the blood glucose level, and providing a more stable blood glucose level over time. Reducing the amount of carbohydrates consumed may also help to lose weight by reducing significantly the number of empty calories.
As used herein, the calorific content is calculated by the use of Atwater caloric conversion factors. The Atwater factors are based on the assumption that each gram of carbohydrate, protein and fat in the diet will yield 4, 4 and 9 calories (kcal) respectively. Those of skill in the art will also understand the term 'empty calories' to refer to foods that supply energy (calories) only, while other nutrients such as minerals, vitamins and proteins are missing or present in very low amounts. Those of skill in the art. will know that commercially available carnitine supplements proven to work typically comprise over 200 calories per gram of carnitine. The low carbohydrate carnitine
supplement advantageously reduces the total number of calories for a serving of the supplement to increase total carnitine accumulation in skeletal muscle. Most preferably, a serving of the low
carbohydrate supplement comprises less than 20 calories derived from carbohydrates, protein and naturally occurring free amino acids per gram of carnitine.
As used herein carbohydrate preferabl refers to food carbohydrates such as simple carbohydrates and polysaccharides and combinations thereof; as well as derivatives thereof such as esters, and amides, as well as other derivatives, including derivatives that become active upon metabolism. Simple carbohydrates may refer to glucose, maltose, sucrose, galactose and lactose or combinations thereof. Advantageously, the simple carbohydrate is glucose and the
polysaccharide is Vitargo© (see EP07 5096B1) . When the carbohydrate is a combination of simple carbohydrate and polysaccharide the preferred ratio is 1 to 1 Most, preferably a serving of the low carbohydrate supplement comprises 3g of carbohydrate per gram of carnitine. Advantageously, the most preferred protein is whey hydrolysate in the ratio of 6g to Ig of carnitine. A preferred non-dairy protein is soy protein. The most preferred naturally occur ing free; amino acids selected from the group of 20 naturally occurring free amino acids comprises 1.44q L-leucine and 1.44g L-Phenylalanine per gram of carnitine.
Additional ingredients which increase carnitine accumulation in skeletal muscle may advantageously be added to the low carbohydrate supplement to further reduce the empty calories. Optionally further additional ingredients may be added to the supplement.
In the most preferred embodiment in a serving of the low
carbohydrate supplement it includes about. 20rng of alpha lipoic acid; 200mg of L-taurine; about 30meg of chromium; about 2g of 4- Hydroxyisoleucine; per gram of carnitine. Those of skill in the art
will appreciate that the supplement may comprise small amounts of free fatty acids either for health benefits or for packaging. Most preferably the supplement comprises less than 3g of fat per serving. In addition the present invention relates to a method of
manufacturing a low carbohydrate supplemental dietary composition that may activate increased levels of fatty oxidation as well as acti ating p otein synthesis machiner and deactivating catabolic processes and in so doing may reduce body fat; improve body
composition and assist in the treatment of muscle and obesity related illnesses or conditions as well as suppressing the effects of sarcopenia in the aging population and provide a range of well documented beneficial cardio-vascular and neuro cognitive effects. Vegetarians will specifically benefit from this invention by ensuring a stabilised supply of carnitine into key body organs such as the heart, kidney tissue and liver.
C&Tnxfcj-Tie ind, c eatine nhBnc&meni: cosnposxt jLons iid the us&s
In accordance with the present invention there is provided a low carbohydrate carnitine with creatine supplement comprising a carnitine source, a protein source, a carbohydrate source and one or more naturally occurring free amino acids wherein a serving of the low carboh drate carnitine/creatine supplement is effective in amplifying carnitine and creatine accumulation in skeletal muscle.
Also provided in accordance with the present invention is a serving of the low carbohydrate carnitine/creatine supplement comprising less than about 20 calories derived from the carbohydrate source, the protein source and naturally occurring free amd.no acids (per gram of carnitine/creatine) selected from the group consisting of L- Leucine and L~Phenylalanine .
Also provided in accordance with the present invention is a method for manufacturing a low carbohydrate carnitine/creatine supplement comprising the step of mixing a carnitine and creatine source, a carbohydrate source, a protein sou ce and a naturally occurring f ee
amino acid, blending and mixing for 30 minutes; and checking for uniformity/homogeneity and then aliquoting into a serving.
The present invention provides a method for activating the protein synthesis machinery and deactivating catabolic processes within skeletal muscle by regulating molecular signals to control anabolic and anti-catabolic activity in skeletal muscle via nutrients including but not limited to amino acids and growth factors. For example, the present invention may provide, by the consumption of a supplemental dieta y composition as set forth herein, a method, for improving body composition, treating muscle wasting or degenerative disease, suppressing the effects of sarcopenia in the aging population and/or providing a beneficial effect by influencing the genetic control system for global, protein synthesis.
Moreover, the present invention also provides a. composition and. methods to increase the level of fat oxidation in humans and in accordance with the present invention will enable dietary
supplements to be manufactured and methodologies employed that find use in the treatment of conditions of the human or animal body associated with a need to reduce excess body fat including
conditions associated with an impairment of fat oxidation, obesity o type 2 diabetes or to assist i energy restriction dietary- regimes that focus on the reduction of body fat.
The present invention also provides for a method of supplementing the diet of an animal, comprising administering to the animal a serving of a low carbohydrate carnitine and creatine supplement comprising carnitine, creatine, carbohydrate, protein and one or more naturally occurring free amino acids .
The present invention also provides a supplemental dietary
composition that may include L~Leucine, including salts or
derivatives thereof, L-phenylalanine, including salts or derivatives thereof, carnitine and/or creatine, including salts or derivatives thereof, and may also include sources of dietary protein and/or carbohydrates . The supplemental dietary composition may also include
one or more of Amylopectin barley starch, dextrose, alpha-lipoic acid ( "ALA" ) , maltodextrin, WPC-80, bitter blocker flavours, citric acid, more flavour, potassium citrate, and sucralose. The
supplemental dietary composition may activate the protein synthesis machinery and deactivate catabolic processes within skeletal muscle by regulating molecular signals to control anabolic and anti- catabolic activity in skeletal muscle. In doing so the supplemental dietary composition may stimulate fatty oxidation, decrease muscle cata olism and improve body composition, treat muscle wasting or degenerative disease, suppress the effects of sarcopenia in the aging population and/or provide a beneficial effect by influencing the genetic control system for global protein synthesis.
In addition, the present invention provides a low carbohydrate carnitine and creatine supplement comprising: carnitine, creatine, carbohydrate, protein and naturally occurring free amino acids wherein a serving of the supplement is effective in increasing carnitine and creatine accumulation in skeletal muscle.
The present invention also provides for a method of increasing carnitine and creatine accumulation in skeletal muscle of an animal comprising the steps of: administering a low carbohydrate carnitine, creatine supplement comprising a serving of carnitine, creatine, carbohydrate, protein and one more naturally occurring free amino acids; and increasing the total muscle carnitine and creatine in the skeletal muscle of an animal .
In addition, the present invention relates to a method, of
manufacturing a supplemental dietary composition that may activate the protein synthesis machinery and deactivate catabolic processes within skeletal muscle by regulating molecular signals to control anabolic and anti-catabolic activity in skeletal muscle, and in doing so, may stimulate fatty oxidation, decrease muscle catabolism, treat, muscle wasting or degenerative disease, suppress the effects of sarcopenia in the aging population and/or provide a beneficial effect by influencing the genetic control, system for global protein s nthesis .
In one embodiment, the method of manufacturing a supplemental dietary composition includes the step of mixing one or more of L- Leucine, including salts or derivatives thereof, L-phenylalanine, including salts or derivatives thereof, carnitine including salts or derivatives thereof and creatine, including salts or derivatives thereof. The method of manufacturing a supplemental dietary composition may also include the step of mixing one or more of Amylopectin barley starch, dextrose, ALA, rnaltodextrin, WPC-80, bitter blocker flavor, citric acid, another flavor, potassium cit ate, sucralose and colouring.
The present invention also provides for a method for manufacturing a low carbohydrate carnitine and creatine supplement comprising:
carnitine, creatine, carbohydrate, protein and. a naturally occurring free amino acid the method comprising the following steps: premixing micro-crystalline cellulose with the following ingredients to the premix: carnitine, creatine, Amylopectin barley starch, dextrose, high quality milk proteins, L-Phenylanine, L-Leucine, and
microcrystalline cellulose; adding magnesium stearate and silica which had been pre-sifted; blending and mixing for 20 minutes; and checking for unifo mity/homogeneity and then aliquot ing i to a serving .
Recent research has demonstrated that key amino acids, e.g., leucine and phenylalanine play an important role as nutrie t signals involved in protein synthesis via mechanisms such as stimulating insulin release which in turn translate to positive influe ces on muscle growth and inhibition of muscle breakdown and by activating molecules involved in protein synthesis. Insulin production via key components as set forth in the present invention and in conjunction with the direct signalling effect of critical amino acids as set forth in the present invention work together to stimulate protein synthesis. Leucine is a key component in this formula noting that it has been found to be the most potent branch chain amino acid for stimulating protein synthesis. More specifically leucine and phenylalanine produce an anabolic signal in combination with the above-described benefits of carnitine and creatine supplementation
is believed to have an additive effect on changing body composition e.g. weight loss and athleticism by the addition of lean mass and reduction of fat mass. Using Leucine, Leucine AKG, Leucine ethyl, ester, N-acetyl-leucine, nor-leucine salts or other derivatives or bound forms of Leucine with or without the addition of simple sugars, Amylopectin barley starch, ALA, maltodextrin, carbohydrates or proteins can elicit an insulin spike that in turn causes the triggering of the mechanism to uplift carnitine and creatine into muscle as well as triggering the protein synthesis pathways necessary for healthy muscle. Using Leucine, Leucine AKG, Leucine ethyl ester, N-acetyl-leucine, nor- leucine salts or other derivatives or bound forms of Leucine with or without the addition of simple sugars, amylopectin barley starch, ALA, maltodextrin, carbohydrates or proteins, e.g. whey protein concentrate can elicit an insulin spike that in turn causes the triggering of the mechanism to uplift carnitine and creatine into muscle as well as triggering protein synthesis pathways that are independent and/or synergistic with the pathways that are through insulin. Using Phenylalanine, Phenylalanine AKG, Phenylalanine ethyl ester, N-acetyl-phenylalanine, salts or any other derivatives or bound forms of phenylalanine with or without the addition of simple sugars, Amylopectin barley starch, ALA, maltodextrin, carbohydrates or proteins, e.g. whey protein concentrate can elicit an insulin spike that in turn causes the triggering of the mechanism to uplift carnitine (and creatine) into muscle as well as triggering protein synthesis pathways that are independent and/or synergistic with the pathways that are through insulin. It is the case that Leucine and phenylalanine directly and indirectly, also may have independent and synergistic effects on protein synthesis that utilize a different pathway than the insulin mediated pathway previously described and thus proving method and supplement for enhancing carnitine/creatine accumulation/retention in humans and enhancing protein synthesis. The ingestion of a high carbohydrate carnitine or creatine
supplement has been shown to result in an increase in total muscle carnitine and creatine uptake and accumulat on as compared with the intake of carnitine or creatine alone. It is believed that the
carbohydrates increase carnitine and creatine uptake by stimulating secretion of insulin. The resulting increase in plasma insulin increases the activity of a sodium-dependent muscle carnitine/ creatine transporter. This is supported by evidence that insulin augments muscle carnitine/creatine accumulation v/hen present at a concentration >75mU/l. It has been unexpectedly found tha the ingestion of a low carbohydrate carnitine with creatine supplement comprising reduced levels of carbohydrate and protein in combination with naturally occurring free amino acids is effective to amplify ei her or both carnitine and creatine accumulation. This increased uptake and accumulation is similar to that observed with a high carbohydrate carnitine/ creatine supplement. The low carbohydrate supplement advantageously reduces the quantity of carbohydrate consumed during carnitine/creatine supplementation, reducing the blood glucose level and providing a more stable blood glucose level over time. Reducing the amount of carbohydrates consumed may also help to avoid weight gain by reducing significantly the number of empt calories . As used herein, the calorific content is calculated by the use of
At ater caloric conversion factors. The Atwater factors are based on the assumption that each gram of carbohydrate, protein and fat in the diet will yield 4, 4 and 9 calories (kcal) respectively. Those of skill in the art will also understand the term ■'empty calories' to refer to foods that supply energy (calories) only, while other nutrients such as minerals, vitamins and proteins are missing or present in very low amounts.
Those of skill in the art will know that commercially available carnitine and creatine supplements typically comprise over 200 calories per gram of carnitine and about 75 calories per gram of creatine. The low carbohydrate carnitine and/or creatine supplement advantageously reduces the total number of calories for a serving of the supplement to increase total carnitine and creatine accumulation in skeletal muscle. Most preferably, a. serving of the low
carbohydrate supplement comprises less than 30 calories derived from
carbohydrates, protein and. naturally occurring free amino acids per gram of carnitine and creatine.
As used herein carbohydrate preferably refers to food carbohydrates such as simple carbohydrates and polysaccharides and combinations thereof; as well as derivatives thereof such as esters, and amides, as well as other derivatives, including derivatives that become active upon metabolism. Simple carbohydrates may refer to glucose, maltose, sucrose, galactose and lactose or combinations thereof.
Advantageously, the simple carbohydrate is glucose and the polysaccharide is Vitargo®. When the carbohydrate is a combination of simple carbohydrate and polysaccharide the preferred ratio is 1 to 1,
Most, preferably a. serving of the low carbohydrate supplement comprises 3g of carbohydrate per gram of carnitine/creatine .
Advantageously, the most preferred, protein is whey hydrolysate in the ratio of 5g to Ig of carnitine and creatine, A preferred non- dairy protein is soy protein.
The most preferred naturally occurring free amino acids selected from the group of 20 comprises 1.44g L-leucine and 1.44g L- Phenylalanine per gram of carnitine/creatine.
Additional ingredients which increase carnitine and creatine accumulation in skeletal muscle may advantageously be added to the low carbohydrate supplement to further reduce the empty calories. Optionally additional ingredients may be added to the supplement.
In the most preferred embodiment in a serving of the low
carbohydrate supplement includes about 20mg of alpha lipoic acid; 200mg of L-taurine; about 30meg of chromium; about 2g of 4- Hydroxyisoleucine; pe gram of carnitine/creatine and less than 3g of fat per serving.
CoBiizyirte A enhstnceitteni co tpos it ions snd the
In accordance with the present invention there is provided a course of servings of the exogenous precursors of coenzyme A (CoASH) synthesis derived from D-pantothenic acid and L-cysteine that is effective in increasing muscle tissue free CoASH concentration.
Also provided in accordance; with the present invention is a course of servings of the exogenous precursers of CoASH synthesis derived from D-pantothenic acid and L-cysteine that is effective in increasing muscle tissue free CoASH concentration, increasing" muscle endurance performance, lowering muscle fatigue and lowering the heart rate during or without exercise.
Also provided in accordance with the present invention is a dietary composition comprising a carnitine or creatine source, a protein source, a carbohydrate source, one or more naturally occurring free amino acids from the group leucine and phenylalanine and exogenous precursers of CoASH synthesis, D-pantothenic acid and L-cysteine wherein a course of the servings is effective in amplifying carnitine or creatine accumulation in skeletal muscle and increases the muscle tissue free CoASH concentration.
According to the present invention there is provided a composition for improving muscle performance during exercise, the composition comprising at least two precursors of coenzyme A synthesis.
According to a further aspect of the present invention there is provided a method of improving muscle performance during exercise: by increasing the coenzyme A pool within the muscle by supplementing the muscle with at least two precursors of coenzyme A synthesis.
According to yet a further aspect of the present invention there is provided a method of improving endurance exercise performance of muscle, the method, comprising the supplementing the coenzyme A pool within the muscle by administering at least two precursors of
Coenzyme A synthesis.
Preferably one of the precursors is D-pantothenic acid or a functionally equivalent derivative thereof.
Preferably the other precursor is L-cysteine or a functionally equivalent derivative thereof.
Preferably the precursors are provided in a composition which may be administered directly to the muscle tissue, or alternatively to a body comprising the muscle, such as by way of ingestion and/or injection.
The composition may be in the form of a food or dietary supplement and may be solid, e.g. powder, tablet , capsule or caplet or may be liquid.
Preferably D-pantothenic acid or a functionally equivalent
derivative thereof, is provided in an amount in the range 0.05g to 5g, and preferably in an amount of approximately 2g. Preferably L-cysteine or a functionally equivalent derivative thereof is provided in an amount in the range 0.05g to 5q, and.
preferably in an amount of approximately 2g.
The precursors may be administered daily in the aforesaid amounts, over a period of several days. The precursors may be administered over a period of between five and seven days and preferably five days or alternatively they may be cidministered continuously over longer periods . Preferably the precursors are provided simultaneously.
According to yet a further aspect of the present invention there is provided a substance comprising pantothenic acid and Cysteine or functionally equivalent derivatives thereof, for use in the manufacture of a medicament, for the treatment of muscle to improve endurance exercise fatigue.
According to yet a further aspect of the present invention there is provided a substance comprising pantothenic acid and Cysteine or f nctionally equivalent de ivatives thereof, for use in the manufacture of a medicament for the treatment of muscle fatigue,
.According to yet a further aspect of the present invention there is provided a substance comprising pantothenic acid and cysteine or functionally equivalent derivatives thereof, for use in the manufacture of a medicament for lowering the heart rate.
In addition, the present invention provides a substance comprising pantothenic acid and cysteine or functionally equivalent derivatives thereof, a low carbohydrate carnitine and creatine supplement comprising: carnitine, creatine, carbohydrate, protein and naturally occurring free amino acids (specifically Leucine and phenylalanine) wherein a serving of the supplement is effective in increasing carnitine and creatine accumulation in skeletal muscle to combine a number of skeletal muscle benefits including but not exclusively fat loss, the preservation of lean muscle mass, a reduction in the heart rate and muscle fatigue and an increase in muscle endurance capacit .
It has been found in accordance with the present invention that increasing the cellular Coenzyme A (CoASH) pool attenuates the competition between carbohydrate and fat oxidation in skeletal muscle tissue and thereby improves fuel oxidation and delays the exhaustion point of the muscle tissue. CoASH is an indispensible cofactor for the pyruvate dehydrogenase complex (PDC) and β-hydroxl acyl-CoA dehydrogenase (β-HAD); the two key enzymes that occupy the rate limiting steps in carbohydrate and fat oxidation respectively. Through their reactions, PDC and β-HAD control the rate of acetyl group supply from carbohydrate and fat to the mitochondria and therefore the rates at which CoASH is utilized. However , the cellular CoASH pool is limited {-45-50 μιηοΐ/kg dry tissue, of which 95% is located within the mitochondria), and during conditions of increased energy demand, its concentration could be markedly reduced thereby limiting the rate of carbohydrate and/or fat oxidation.
The fuel that skeletal muscle uses during exercise depends upon the intensity and duration of the exercise to which the rnuscle is exposed. Low intensity exercise, i.e. exercise using less than half of the physical abilities of the muscle, uses fat as the predominant fuel and therefore fat oxidation is the primary metabolic reaction fueling the muscle. Fat reserves, particularly in the human body, are generally quite large such that the availability of fat as a fuel is unlikely to limit the performance at such low intensity 1eve;Is.
However, as exercise intensity increases, then the source of fuel switches from fat to carbohydrate, mainly in the form of stored glycogen. In the average human body, the amount of stored glycogen is limited. Therefore at physical exercise intensities of between
60%~85% of VC max of that, body, the amount of exercise that the muscle can perform is generally restricted by the level of muscle glycogen reserves . It has been established in accordance with the present invention, that increasing the muscle cellular coenzyme A (CoASH) pool reduces the competition between carbohydrate and fat oxidation in skeletal muscle tissue, resulting in an improvement in fuel oxidation and importantly enabling the muscle to continue exercising beyond the 'natural' exhaustion point. The present invention therefore; provides for an improvement in the physical performance of muscle
particularly skeletal muscle;, during exercise. The invention may also help in the treatment of muscle disorders that impair muscle performance and may help in alleviating muscle fatigue. This could have very many advantages and uses particularly for people or animals required to undertake prolonged work or exercise or who are required to partake in exercise in conditions where food supplies may be intermittently available or otherwise limited. The muscle tissue free CoASH concentration or pool is increased in accordance with the p esent invention by providing exogenous precursors of CoASH synthesis, D~pantothenic acid and L~-cysteine.
The D~pantothenic acid and/or L-cysteine may be replaced by functionally equivalent derivatives thereof. The D-pantothenic acid and L-cysteine or functionally equivalent derivatives, may be provided in a composition for oral administration to a body comprising the muscle, or may be provided in any other suitable form, e.g. solid or liquid, for alternative administration to the body comprising the muscle tissue, or directly to the muscle tissue itself .
The D-pantothenic acid may, in some cases, be provided in an amount within the range O.OSgms to 5gms.
The L-cysteine may, in some cases, be provided in an amount within the range O.OSgms to 5gms .
The precursors may be administered over a period of several days for example 5-7days. The precursors may be administered continuously over longer pe iods.
The precursors are preferably administered simultaneously, although it is within the scope of the present invention for them to be administered separately, e.g. sequentially.
Exanigles
Example 1 — Supplementation with CoA precursors im ro es exercise performance
The following is a description of the experimental protocol and methodology conducted and from which the data provided in figure 2 was obtained. Eighteen normal, healthy, young human male volunteers aged 18 years - 25 years participated in this study (mean+/-SE : age 21.3+/-0.3, height 177+/-2cm, body weight 74.9+/-3 , 0kg)
Firstly the subjects performed an intermittent incremental exercise test to exhaustion on an electrically braked cycle ergorneter during which expired gases were collected to measure
One week later the subjects returned to confirm their V02max and to become familiarised with cycling at a fixed exercise workload, of 75%
V02max .
Following an overnight fast, the subjects cycled again on an electrically braked cycle ergorneter to the point of exhaustion (60- 90mins) at an intensity of 75% of their V02max during which time gas exchange (W02, V02 ) , respiratory exchange ratio (RER) and heart rate were monitored for 2 minutes and 5ml. blood, samples were obtained (via an indwelling cannula placed in the back of their hand prior to the start of the exercise) every 20 minutes and at the point of exhaustion. Exercise was stopped at the point at which the subjects could not. maintain a. pedal frequency of 50 revs/'min and this time was recorded (this was the measure of exercise
performance) - see figure 1, Following one week of normal activity and dietary intake, the subjects were randomly split into 2 groups of 9 subjects. The subjects in each group were each given either 2g each of daily supplements of pantothenic acid, and L-cysteine in the form, of capsules or a placebo { g of glucose polymer/day) over the next five days. At the end. of the supplement period subjects returned to the laboratory following an overnight fast to repeat the exercise performance protocol described in the preceding paragraph.
As can be seen from the results plotted, in figure 2, following five days of supplementation with precursors of CoASH synthesis, i.e. pantothenic acid and L-cysteine a significant improvement in the exercise performance (duration) was observed.
Furthermore during the exercise the heart rates of the subjects whose diet 'was supplemented with CoASH precursors for five days 'was significantly lower compared with the pre-supplementation group .
It has therefore been shown, i accordance with the present, invention, that supplementation with pantothenic acid and L- cysteine, acts to increase coenzyme A availability within muscle tissue which in turn has beneficial effects on fat and carbohydrate fuel utilization and skeletal muscle performance during exercise, and in particular has beneficial effects on muscle endurance performance. This will enable the muscle to endure longer periods of operation . Example 2 - Carnitine + Vitargo®
It has been found that insulin increases muscle total carnitine (TC) content during acute i.v. L-carnitine infusion. Here we determined the effects of carnitine and Vitargo® in a specific recipe. On two occasions, 14 healthy, moderately trained, male volunteers
(age 25.9 ± 2.1 yr, ΒΜΪ 2.3.0 ± 0.8 kg/m") performed an exercise test comprising 30 min cycling at 50% and 80% V02maxr followed by a 30 min work output performance trial. Muscle biopsies were obtained at rest and. after exercise at 50% and 80% V02lisx on each occasion. Following the first exercise visit, volunteers ingested either 80g of Vitargo® (CHO; Control) or 2 g of L-carnitine and 80 g of Vitargo® twice per day for 24 wk in a randomised, double blind manner.
Carnitine ingestion increased muscle total carnitine by 20% {22 ± 1.1 to 26.7 ± 2.4, P<0.05), whilst the control was unchanged. At 50% V02max; the carnitine group exhibited 55% less muscle glycogen ut.i1isation (26.9 ± 4.4 vs 60.3 ± 9.4 mmo1 -kg"1dry mu sc1e { d ) , respectively, P<0,05) and 30% less activation of the pyruvate dehydrogenase complex (PDC, 0.5 ± 0.1 vs 0.7 ± 0.1 mmol acetyl CoA/min"kg~'wet muscle (wm) , respectively, P<0.05) compared to
Control. Conversely, at 80% yo2raai, muscle PDC activation status was 45% higher (2.3 ± 0.2 vs 1.6 ± 0.1 mmol acetyl CoA/min-kg'1 wm, respectively, P<0.05) , acetylcarnitine content was 16% greater (18.4 ± 1.7 vs 15.8 ± 1.4 mmol 'kg"1 dm, respectively, P<0.10) and muscle lactate content was 44% lower {25.0 ± 4.1 vs 44.4 ± 6.9 mmol "kg"1 dm, respectively, P<0.05) in Carnitine compared to Control. The;
Carnitine group also demonstrated a 10% increase in work output from
baseline in the performance trial (343 ± 20.0 vs 310 ± 26.8 KJ, respectively, P<0.01) , whilst work output was unchanged in control.
Example 3 - Creatine + Carnitine supplementation
Aim: The aim of the study was to identify a supplement/composition that would optimise the augmentation of creatine (Cr) and carnitine (Ca) through consuming a lower carbohydrate load. Methods :
Study Design: Randomised double-bind, placebo controlled, cross-over design. Ethical approval: This study was approved by the University of Nottingham. Medical School Research Ethics Committee.
Volunteers: 7 healthy male volunteers. All volunteers were medically screened and eligible to participate.
Protocol: The volunteers were required to attend the lab for 3 trials. Each consisted of a morning and an afternoon attendance each lasting for approximately 4 hours. Volunteers were required to rest on a bed. A baseline blood sample was taken. Each trial was administered via a nasogastric tube over an approximate time of 7 minutes. After a 3 hour protocol a second trial solution was administered. A third solution was administered in the following morning trial. Each trial was separated by 12 days.
Blood sampling: Blood samples were collected for 3 hours after administration of the solution. Eleven blood samples were obtained at 15 minute intervals during the first hour then increasing to 20 minutes for the next, two hours. Approximately 3ml of blood was transferred to a lithium heparin containing tube and a further 3ml was allowed to clot, for plasma, and insulin analysis.
It is now known that, insulin promotes muscle carnitine accumulation in healthy young volunteers but required a high physiological insulin concentration to be maintained to achieve this effect. This effect is demonstrated by increased fat oxidation at lower to medium intensity physical activities and a significant reduction in lactate accumulation at high intensity physical activities and these effects are especially advantageous in the context of sport and exercise where energy demands are invariably high, However, in the context of health and well-being including energy restriction dieting, it would more advantageous in the general public to have a lower carbohydrate and caloric load composition producing the same effects whilst at the same time maintaining high insulin (lower blood glucose levels) in the form of an ingredient technology. With this in mind further laboratory studies were carried out linked to other metabolic and gene expression studies to produce an oral nutritional formulation with a physiologically high insulinaemic response (>75 mU/1 ) , but with a relatively low caloric and carbohydrate load (Vitargo + Vitargo/Maltodextrin) to determine if a precise formulation could be applied to achieve the same fat and fuel utilisation effects. These values are as recorded in the creatine + carnitine (Cr + C) studies.
The multiple studies referred to are also cross referenced into (i) stud work concerning the activation of genes encoding proteins that regulate muscle fat oxidation from a pre -determined cohort of 170 genes known to regulate muscle fat and carbohydrate; oxidation and; (ii) , aetiology of intra-muscular lipid (ILM) accumulation and muscle insulin resistance in older age groups to determine if this proposed low caloric method can dampen negative age related responses. The objective of the direction of the studies noted is to produce a range of diverse market formulations for categories such as diet and weight loss and expanding into clinical markets associated with conditions such as type 2 diabetes and other obesity linked conditions .
Example 5 ~ Carnitine uptake in vegetarian and non-vegetarian
■„."". .S.„..„.„,
Background: Ninety-five percent of the body carnitine pool resides in skeletal muscle where it. plays a vital, role in fuel metabolism.. However, vegetarians obtain negligible amounts of carnitine from their diet.
Objective: We tested the hypothesis that muscle carnitine uptake is elevated in vegetarians compared with that in non-vegetarians to aintain a norma1 tiss e ca nitine content .
Design: Forty-one young (aged --22 y) vegetarian and non-vegetarian volunteers participated in 2 studies. The first study consisted of a 5-h intravenous infusion of L-carnitine while circulating ins lin was maintained at a physiologically high concentration (~170 mU/L; to stimulate muscle carnitine uptake) or at a fasting concentration (—6 rnU/L). The second study consisted of oral ingestion of 3 g L-carnitine .
Results: Basal plasma total carnitine (TC) concentration, 24-h urinary TC excretion, muscle TC content, and muscle carnitine transporter [organic cation transporter 2 (OCTN2 ) ] messenger RNA and protein expressions were 16% (P < 0.01), 58% (P < 0.01), 17% (P < 0.05), 33% (P < 0.05), and 37% (P = 0.09) lower, respectively, in vegetarian volunteers. However, although non-vegetarians showed a 15% increase (P < 0.05) in muscle TC during L-carnitine infusion with hyperinsulinemia, L-carnitine infusion in the presence or absence of hyperinsulinemia had no effect on muscle TC content in vegetarians. Nevertheless, 24-h urinary TC excretion was 55% less in e eta ians after L-carnitine ingestion.
Conclusions: In conclusion, in contrast to our hypothesis, it appeared that healthy vegetarian volunteers had a reduced capacity to uptake carnitine into the skeletal muscle (which is the main store of carnitine within the body) because of an adaptation of OCTN2 to lowe muscle carnitine stores to conserve carnitine for other tissues. These findings could have important implications for patients on long-term carnitine-free parenteral nutrition or hemodialysis treatment who become carnitine deficient over time (25- 27) . With this in mind, one of the participants in the current study
returned to an omnivorous diet after 11 y as a vegetarian and his plasma and muscle TC values had returned to normal after 6 months.
Example 6 - Additional study of CoA precursor supplementation
This study attempted to increase the muscle CoASH pool in humans, via pantothenic acid and. c steine feeding, in order to elucidate he role of CoASH availability on muscle fuel metabolism during exercise specifically aimed at a sporting context. However, a by-product of the study was observed that was totally unexpected in the form of a significant reduction in the heart rate in the group being fed on the CoASH precursers as shown in Figure 2 and has significant potential in the context of health and well-being.
STUDY METHODS
On 3 occasions eight healthy, non-smoking, non-vegetarian,
recreationally active males (age 22.9 ± 1.4 yr ; body mass 75.6 ± 4.8 kg; body mass index 24.2 ± 1.5 kg/irr4; V" o2max 47.7 ± 2.5 ml - kg""1 · min"1) participated in this study. The study was approved by the University of Nottingham Medical School Ethics Committee in accordance; with the Declaration of Helsinki. Prior to the study, each subject completed a routine medical screening and a general health questionnaire to ensure their suitability to take part. All gave their written consent to participate in the study and were aware that they were free to withdraw from the experiment at any time.
Volunteers reported to the laboratory on three occasions over a 6-wk period, each visit being separated by 2 wk . The protocol for each of these visits is depicted in Figure 1. Subjects arrived after an overnight fast having abstained from strenuous exercise and alcohol consumption for at least 48 h, and caffeine for at least 24 h. On arrival at the laboratory on each visit, subjects were weighed, voided their bladder, and. then rested in a semisupine position wh le a cannula was inserted into an antecubital vein in the nondominant arm for subsequent venous blood collections. Volunteers then underwent a glycogen-depleting exe cise protocol consisting of continuous bicycling exercise for 60 min at 75% of V*02MS followed
by intermittent exercise at the same intensity until volitional exhaustion. {It had been previously shown that this protocol is effective at. reducing mixed fiber muscle glycogen content to <80 mmol/kg dry muscle) . Exhaustion was defined as the inability to maintain 70 rpm on the cycle ergometer for 1 min immediately follow min rest period. The time taken to reach exhaustion was recorded for the first visit (totalling 91.3 ± 3.1 min of exercise) and repeated for the two subsequent visits with the timing of rest periods kept identical. At the point of exhaustion, subjects were; permitted a 5-min rest after which they performed a 15-min work output <kJ) performance test. This "all-out" performance test involved usi g the ergometer line r mode function, where work output is dependent on volitional cycling cadence. {See Figure 1.) Volunteers began 1 wk of oral supplementation with either 1.5 g/day each of L-cysteine and D-pantothenic acid (CP; Holland, and Barrett, Warwickshire, UK) , or 3 g/day of a glucose polymer control (CON; Maxijul, UK). Following the visit and a. further 2-wk rest/washout period volunteers repeated the supplementation protocol. The order of the supplementation was randomized and counterbalanced in a double-blind manner. A 2-wk recovery/ ashout period was selected because it has previously been shown that ~80% of an oral
pantothenic acid dose is eliminated from the body within 5 days
DISCUSSION
As it is known that the ingestion of CoASH per se results in its prompt degradation to its precursors within the gut, and. whereas dietary pantothenic acid is readily absorbed primarily via a saturable, sodium-dependent active transport process, accordingly, the approach of feeding CoASH precursors described herein was adopted. Thus pantothenic acid supplementation was employed in an attempt to drive CoASH formation and cysteine ingestion simply to be sure no deficiency existed.
Coenzyme A (CoASH) fulfills several distinct roles in muscle energy metabolism. First, as a substrate for the enzyme acyl-CoA synthetase {ACS), CoASH allows the activation of cytosolic fatty acids to fatty acyl-CoAs before their subsequent delivery to the mitochondria via
the carnitine shuttle system.. Second, in the final stage of the carnitine shuttle system, mitochondrial CoASH is required for the carnitine palmitoyltransferase 2 (CPT2) -mediated transesterification of acylcarni tine to carnitine and acyl-CoA. Third, a viable supply of free CoASH is necessary for the final stage of mitochondrial fatty acid β-oxidation, where β-ketoacyl-CoA is sequentially cleaved by the thiol group of another molecule of CoASH to form acetyl-CoA and acyl-CoA. Fourth, the pyruvate dehydrogenase complex (PDC)- mediated oxidative decarboxylation of pyruvate to acetyl-CoA also requires an available pool of mitochondrial free CoASH. Finally, free CoASH is also a key substrate for a-ketoglutarate dehydrogenase within the tricarboxylic acid (TCA) cycle and is therefore necessary for TCA flux. Despite these well-documented roles, the influence of muscle CoASH availability on skeletal muscle fuel, metabolism during exercise in humans remained to be less than fully understood.
The aim of the study therefore was to elevate the muscle free CoASH pool in healthy humans via 7 days of oral supplementation with pantothenic acid and cysteine {precursors of endogenous CoASH biosynthesis) in order to further elucidate the role of CoASH availability in the regulation of muscle fuel metabolism during exercise. In keeping with this hypothesis, 1 wk of dietary
pantothenic acid supplementation (1.5 g/day) has previously been shown to reduce blood lactate concentration compared with control during steady-state exercise at 75% Vo2iMX however, the underlying mechanism within skeletal muscle was not investigated. Finally, it was hypothesized that if pantothenic acid and cysteine
supplementation could impact on muscle CoASH availability and muscle fuel metabolism during exercise, irrespective of the mechanism by which the latter was achieved, it could reasonably be expected to increase work, output, during a. subsequent exercise performance test.
Thus it was not immediately obvious why unexpected results were obtained. Specifically it is thought the in vivo situation
represents a much more complex physiological milieu, however, it therefore seems likely that the significant reduction in heart rate
could be related to a combination of metabolic and cardiac processes as yet to be fully investigated.
Example 7 - Protein hydrolysate insulinotropic response
The insulinotropic response; to the ingestion of whey protein and whey protein hydrolysate, independent of carbohydrate, is not known. This study examined the effect of protein hydrolysis on the
insulinotropic response to the ingestion of whey protein. Sixteen healthy males ingested a 500 ml solution containing either 45 g of whey protein (WPI) or whey protein hydrolysate (WPH) . The estimated rate of gastric empting was not altered by hydrolysis of the protein [18 (3) vs. 23 (3) min, n=16 P = 0.15] . Maximum plasma insulin concentration (Cmax) occurred later {40 vs. 60 min) and was 28% [234 (26) vs. 299 (31) mM, P = 0.018] greater following ingestion of the WPH compared to the WPI leading to a 43% increase [7.6 (0.9) vs. 10.8 (2.6) nM.3h, P = 0.21] in the AUG of insulin for the WPH. Of the amino acids with known insulinotropic properties only Phe demonstrated a significantly greater maximal concentration [Cmax; 55 (2) vs. 72 (3) uM, n=16; P = 0.01] and an increased (+22%) AUG following ingestion of the WPH.
In conclusion, ingestion of whey protein is an effective insulin secretagogue . Hydrolysis of whey protein prior to ingestion augments the maximal insulin concentration by a mechanism that is unrelated to gastric emptying of the peptide solution.
INTRODUCTION
The essential amino acids (EAA) are the primary regulators of the protein-mediated insulin response (Floyd et al . , 1966) and are heterogeneous in their insulinotropic potency. The milk protein, whey, is a rich source of EAAs . Addition of whey protein to a carbohydrate drink enhances the insulin response to that attained by ingestion of carbohydrate alone (Van Loon et al., 2000).
Furthermore, addition of a whey protein hydrolysate (WPH), rather than the intact protein, to a carbohydrate drink e erts an e en greater insulin response (Calbet and MacLean, 2002) . Emerging data
suggest that the insulinotropic response is dependent on the both the source (whey vs. soy) and degree of hydrolysis of the protein used (Claessens et al., 2008).
The mechanism by which ingestion of protein, protein hydrolysate or AAs, increase insulin secretion is, as yet, equivocal.
AIMS
The aim of this study was to determine the insulinotropic response following ingestion of native and hydrolysed whey protein and to evaluate whether a difference exists in two of the primary
regulators of this response, i.e. the rate of gastric emptying (GE) and. the ci culati g concentration of amino acid of known
insulinotropic potency. METHODS
With ethical approval and informed consent, 16 healthy males (mean { SEM; n=16) 22.4 (0.48) y, 23.2 (0.6) kg,m-2) with no history of gastrointestinal disorders participated in a randomised
intervention, each trial separated by a period of 7 d. Following an overnight fast, subjects ingested whey protein isolate (WPI;
Isolac®, Carbery Food Ingredients, Ireland) or whey protein hydrolysate, 30% DH {WPH; Optipep 80™, Carbery Food Ingredients, Ireland) . While subjects remained seated, pre- and post-prandial blood samples, were withdrawn for a period of 3h (Fig. 1) , Samples were: batch analysed for amino acids and paracetamol (HPLC) , glucose (ELISA) and insulin (RIA) . All data are presented as mean (SEM; n=16). The effect of hydrolysis on each variable was examined and the percent difference calculated, relative to the WPI . The effect of the degree of hydrolysis of whey protein on the variables of interest was examined using a paired-samples t test.
All analyses were performed using SPSS (SPSS Inc, Chicago, IL) .
No difference in the half time (T50%) of gastric emptying was observed (23 vs. 20 min for the WPI and WPH). During the postprandial period the peak concentration (Cmax) and AUC of plasma amino acids was generally lower after ingestion of the WPH except for phenylalanine which showed a marked increase for WPH. Distinct differences in the plasma insulin response were observed for the WPI and WPH (Figure 3). Maximal values were 28% greater [234(26) vs. 299
(31) pM; P = 0.018] after ingestion of the WPH and over the entire 3 hours the area under the curve (AUC) was 43% greater [7.6 (0.9) vs. 10.8 (2.6) nM.3h~l; P =0.21]. Plasma glucose concentration "varied little in the initial 30 min. however during the hyperinsulinemic phase glucose concentration decreased for both whey proteins .
Reg ession analysis revealed a poo correlcition between the magnitude of the plasma insulin and Phe response following ingestion of native [WPI; r = 0.12, P = 0.3] and hydrolysed [WPH; r = 0.19, P = 0.3] whey protein. No relationship was found between the change in plasma BCAAs and insulin after ingestion of the native whey protein
[WPI r= 0.56, P = 0.013] and hydrolysis did not strengthen this relationship [WPH r = -0.04, P = 0.5].
CONCLUSION
In this study oral ingestion of 45g of whey protein was found to be an insulin secretagogue . The resultant hyper insulinemia was glucose independent and, as demonstrated by a significant mean increase in Cmax of 28%, was augmented by hydrolysis of the protein. These data support the contention that the insulinotropic potency of hydrolysed whey protein may provide nutraceutical benefit in a clinical setting where the glucose sensing capacity of the pancreatic β-cell is reduced i.e. type 2 diabetes (Manders et al., 2006).
Example 8 ~ Carnitine supplementation nullifies the fat gain effect
The effect of carnitine supplementation (with Vitargo®) on
carbohydrate over-feeding-induced fat gain was investigated (see
Figure 4), A 20% increase in muscle: carnitine content, achieved via 12 weeks of twice daily supplementation of a beverage containing the technology, prevented an 18% increase in body fat mass associated with carbohydrate supplementation alone in healthy young men.
Body mass and whole-body fat mass (dual-energy X-ray absorptiometry) increased over 12 weeks in Control by 1.9 and 1.8 kg, respectively but did not change In technology group (see Figure 4). A novel finding of the study was that this prevention of fat gain was associated with a greater energy expenditure and fat oxidation during low-intensity physical activity, and an adaptive increase in expression of gene networks involved in muscle insulin signalling and fatty acid metabolism.
This result is of particular significance because it is presently believed that no previous studies have reported weight loss following L-carnitine supplementation without carbohydrate (Stephens et ai . 2001b) . Added support comes from a 14 person study. A pathway-focussed, quantitative, RT-PCR-based low-density array was used to determine coordinated expression of genes involved in the regulation of muscle fuel metabolism. The relative mP.KA abundance: of 73 of the 187 genes measured was increased in the Carnitine group compared with Control after 12 weeks, with gene
functional analysis highlighting 'insulin signalling', 'PPAR signalling'' and 'fatty acid metabolism' as the three most enriched functional pathways.
In conclusion, this is the first demonstration that increasing skeletal muscle carnitine content in healthy humans can modulate energy metabolism over a prolonged period, as reflected by a prevention of an increase in adiposity in abdominal and leg regions,
an increase in energy expenditure during low-intensity exercise, and a robust increase in the expression of rnetabolic genes regulating muscle fuel selection in response to 12 weeks of carbohydrate overfeeding .
These results have particular significance for the promotion of well-being and avoidance of body fat gain among, in particular, a low or non-exercise population and/or those consuming excess carbohydrate in their diet. Without wishing to be bound by any particular theory, the present inventor believes that the
enhancement of fatty acid metabolism induced by the carnitine uplift achieved by the dietary compositions of the present invention mitigates the adverse effect of excessive carbohydrate consumption. The evidence shows that increased carnitine skeletal muscle content as a result of supplementing one's diet with the dietary
compositions of the present, invention nullifies the effect of additional/excess calories consumed to achieve a "zero calorie" effect. This has clear benefits in the context of dieting, well- being, as well as in the treatment of obesity and obesity-related conditions. Moreover, the improved body composition, in particular fat loss or prevention of fat gain, is beneficial in the context of athletic performance and training.
Equivalents^
The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the invention. The present invention is not to be limited in scope by examples provided, since the examples are intended as a single illustration of one aspect of the invention and other functionally equivalent embodiments are within the scope of the invention, arious modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. The advantages and objects of the invention are not necessarily encompassed by each embodiment of the invention.
The entire contents of the earlier patent, applications, GB1217057.7, GB1217582.4 and GB1217163.3, from which priority is claimed, are expressly incorporated herein by reference. All references, including patent documents, disclosed herein are i co porated by reference i their entirety for all purposes, particularly for the disclosure referenced herein,
Arenas, J. , Ricoy, J.R. , Encinas, A.R., Pola, P., D'Iddio, S.,
Zeviani, M., Didonato, S., and Corsi, . 1991 Carnitine in muscle, serum, and. urine of nonprofessional athletes: effects of physical exercise, training, and L-carnitine administration. Muscle Nerve 14, 598-604.
Brass, E.P., Hoppel, C.L., and Hiatt, W.R. (1994) Effect of intravenous L~carnitine on carnitine homeostasis and fuel metabolism during exercise in humans . Clin Pharmacol Ther 55, 681-692. Casey A., Constantin-Teodosiu D., Howell S., Hultman E. and
Greenhaff P.L. ingestion favourably affects performance and muscle metabolism during maximal exercise in humans . Am. J. Physiol. 271: E31-E37, 1996. Fritz, I.B., and. McEwen, B. (1959) Effects of carnitine on fatty- acid oxidation by muscle. Science 129, 334-335.
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Roepstorff, C, Halberg, N . , Hillig, T . , Saha, A.K., Ruderman, N.B., Wojtaszewski, J.F., Richter, E.A., and Kiens, B. (2005) Malonyl-CoA and carnitine in regulation of fat oxidation in human skeletal muscle during exercise. Am J Physiol 283, E133-E142.
Stephens, F.B., Constantin-Teodosiu, D. , Laith aite, D. , Simpson E. J. , and Greenhaff P.L.. Insulin stimulates L-carnitine
accumulation in human skeletal muscle. FASEB J. (2005) 20: 377-9. van Loon, L. J. , Greenhaff, P.L,, Constantin-Teodosiu, D., Saris, .H. , and Wagenmakers, A.J. (2001) The effects of increasing exercise intensity on muscle fuel utilisation in humans. J Physiol 536, 295-304.
Wachter, S., Vogt, M. , Kreis, R. , Boesch, C. , Bigler, P., Hoppeler, H. , and Krahenbuhl, S. (2002) Long-term administration of L— carnitine to humans: effect on skeletal muscle carnitine content and physical performance. Clin Chim Acta 318, 51-61.
Claessens, M . , w.H.M. Saris & M.A.V. Baak (2008) Glucagon and insulin responses after ingestion of different amounts of intact and hydrolysed proteins. British Journal of Nutrition 100: 61-69. Van Loon, L.J., W. Saris, H. Verhagen & A. Wagenmakers (2000) 'Plasma insulin response after ingestion of different amino acid or protein mixtures with carbohydrate', American Journal of Clinical Nutrition,, 72, 96-105.
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Claims
1. A dietary composition comprising:
(i) a carnitine source; and
(ii) (a) free L-leucine, or a salt or amino acid derivative thereof, and/or (b) free L-phenylalanine, or a salt or amino acid derivative thereof.
2. The dietary composition according to claim 1, wherein said free L-leucine or salt or amino acid derivative thereof is selected, from the group consisting of: L-leucine, leucine alpha ketoglutarate, leucine ethyl ester, N-acetyl-leucine and nor-leucine salt.
3. The dietary composition according to claim 1 or claim 2, wherein said free L-phenylalanine or salt or amino acid derivative thereof is selected from the group consisting of: L-phenylalanine,
phenylalanine alpha ketoglutarate, phenylalanine ethyl ester and N- acetyl-phenylalanine.
4. The dietary composition according to any one of the precedi claims, wherein the composition comprises bot L-leucine and L- phenylalanine .
5. The dietary composition according to any one of the preceding claims, wherein L-leucine is present in an amount within the range 0.1 to 9.0 g per g of carnitine.
6. The dietary composition according to claim 5, wherein L-leucine is present in an amount within the range 0.2 to 7.5 g per g of carnitine.
7. The dietary composition according to claim 6, wherein L-leucine is present in an amount within the range 1 to 6 g per g of
carnit ine .
8. The dietary composition according to claim 7, wherein L-leucine is present at about 1.44 g per g of carnitine.
9 , The dietary composition according to any one of the preceding claims, wherein L-phenylalanine is present, in an amount within the range 0.1 to 9.0 g per g of carnitine.
10. The dietary composition according to claim 9, wherein
L-phenylalanine is present in an amount within the range 0,2 to 7,5 g per g of carnitine.
11. The dietary composition according to claim 10, wherein
L-phenylalanine is present in an amount within the range 1 to 6 g per g of earnit ine .
12. The dietary composition according to claim 11, wherein
L-phenylalanine is present at about 1.44 g per g of carnitine.
13. The dietary composition according to any one of the preceding claims wherein one or more servings of the composition is effective to enhance carnitine accumulation in skeletal muscle, liver and/or kidney tissue in a mammalian subject.
14. The dietary composition according to any one of the preceding claims, fu ther comprising creatine or a salt the eof.
15. The dietary composition according to claim 14, wherein the creatine is present in an amount within the range 0.1 to 9,0 g per g of carnitine:.
16. The dietary composition according to claim 15, wherein the creatine is present art about 1:1 ratio by weight to carnitine.
17. The dietary composition according to any one of claims 14 to 16, wherein one or more servings of the composition is effective to enhance creatine accumulation in skeletal muscle in a mammalian subject.
18. A dietary composition comprising D-pantothenic acid, and L- cysteine .
19. The dietary composition according to claim 18, wherein D- pantothenic acid is present, in an amount within the range 0.05 g to 5 g.
20. The dietary composition according to claim 18 or claim 19, wherein L-cysteine is present in an amount within the range 0.05 g to 5 g.
21. The die ary composition according to any one of claims 18 to 20, wherein one or more servings of the composition is effective to enhance coenzyme A accumulation in muscle tissue in a. mammalian subject.
22. A dietary composition according to any one of claims 1 to 17, further comprising D-pantothenic acid and L-cysteine.
23. The dietary composition according to claim 22, wherein D- pantothenic acid, is present in an amount, within the range 0.05 g to 5 g per g of carnitine.
24. The dietary composition according to claim 18 or claim 19, wherein L-cysteine is present in an amount within the range; 0.05 g to 5 g.
25. The dietary composition according to any one of claims 22 to 24, wherein one or more servings of the composition is effective to enhance coenzyme A accumulation in muscle tissue in a mammalian sub ect .
26. The dietary composition according to any one of the preceding claims further comprising at least one carbohydrate.
27. The dietary compositio according claim 26, wherein he at. least one carbohydrate comprises Vitargo®.
28. The dietary composition according to claim 26 of claim 27, wherein the at least one carbohydrate comprises a carbohydrate selected from the group consisting of: glucose, maltose, sucrose, galactose and lactose.
29. The dietary composition according to any one of claims 26 to 28, wherein the amount of carbohydrate is within the range 0.1 to 9.0 g per g of carnitine.
30. The dietary composition according to claim 29, wherein the composition is provided in the form of a low carbohydrate serving having not more than 3 g carbohydrate per g of carnitine.
31. The dietary composition according to any one of the preceding claims, further comprising a protein.
32. The dietary composition according to claim 31, wherein the amount of protein is in the range 0.1 to 9.0 g per g of carnitine .
33. The dietary composition according to claim 32, wherein the amount of protein is in the range 0,2 to 7,5 g per g of carnitine.
34. The dietary composition according to claim 33, wherein the amount of protein is in the range 1 to 6 g per g of carnitine.
35. The dietary composition according to any one of claims 31 to 34, wherein the protein comprises whey hydrolysate .
36. The dietary composition according to any one of claims 31 to 34, wherein the composition is non-dairy and the protein comprises soy protein.
37. The dietary composition according to any one of the preceding claims, wherein the composition is provided in the form of a serving having less than 30 calories derived from carbohydrates, protein and
naturally occurring free amino acids per g of carnitine and, if present, creatine,
38. The dietary composition according to any one of the preceding claims wherein the composition is provided in the form of a serving havi g not more than 3 g of fat.
39. The dietary composition according to any one of the p eceding claims, wherein the composition further comprises one of more of the following: amylopectin barley starch, alpha-lipoic acid ("ALA"), maltodextrin, dextrose, WPC-8G, one or more flavourings, colouring, citric acid, potassium citrate, L-taurine, chromium, 4- hydroxyisoleucine and sucralose.
40. The dietary composition according to claim 39, wherein ALA is present at an amount, in the range 1-100 g or 5-50 mg per g of carnitine .
41. The dietary composition according to claim 40, wherein the composition comprises about 20 mg ALA, 200 mg L-taurine, 30 mg chromium and about 2 to 4 q 4-hydroxyisoleucine per g of carnitine.
42. An article of manufacture comprising packaging housing a plurality of discrete servings of the dietary composition according to any one of the preceding clai s and, optionally, a label or insert with instructions regarding dose and or frequency of said servings .
43. A food, or drink product incorporating the dietary composition according to any one of claims 1 to 41.
44. A dietary composition according to any one of claims 1 to 41 for use in a method of medical treatment.
45. A dietary composition according to any one of claims 1 to 1 for use in a method of treatment of obesity, metabolic syndrome,
muscle wasting, diabetes, sarcopenia, degenerative disease and/or muscle fatigue.
46. A method of treatment of a mammalian subject having obesity, metabolic syndrome, muscle wasting, diabetes, sarcopenia,
degenerative disease: and/or muscle fatigue, said method comprising administering a dietary composition according to any one of claims 1 to 41 to the mammalian sub ect in need thereof.
47. use of a dietary composition according to any one of claims 1 to 41 in the supplementation of a vegetarian diet of a mammalian su j ect .
48. A method of enhancing athletic performance of a mammalian subject, comprising administration of one or more servings of the dietary composition according to any one of claims 1 to 41 to the subj ect .
49. A method of reducing absolute body fat and/or relative body fat per unit of lean body mass, comprising adm.inistrat.ion of one or more servings of the dietary composition according to any one of claims 1 to 41 to the subject.
50. A method for producing a dietary composition according to any one of claims 1 to 41, comprising:
providing a carnitine source and one or both of: (i) a source of leucine, or a salt or derivative thereof, and (i ) a source of phenylalanine, or a salt or derivative thereof;
mixing and/or blending the ingredients to uniformity; and optionally aliquoting the resulting dietary composition mixture into a plurality of servings .
51. The method according to claim 50, wherein the ingredients further comprise one or more of the following: creatine,
D~pantothenic acid, L-cysteine, carbohydrate, vitargo®, glucose, protein, whey protein hydrolysate, soy protein, amylopectin barley starch, alpha-lipoic acid ("ALA") , maltodextrin, dextrose, PC-80,
flavour, citric acid, potassium citrate, colouring, L-taurine, chromium, 4-hydroxyisoleucine and sucralose.
52. The method according to claim 51, wherein the method comprises the steps :
premixing macrocrystalline cellulose with carnitine,
amylopectin barley starch, dextrose, high quality milk proteins, L-pheny1alanine and L-leucine ;
adding magnesium stearate and silica v/hich have been pre- sifted;
blending and mixing- for about 20 minutes;
checking for uniformity/homogeneity; and
aliquoting into one or more servings.
53. A method for producing a food or drink product, comprising the step of incorporating the dietary composition according to any one of claims 1 to 41 into a food or drink mixture at a stage prior to the final packaging of the food or drink mixture to form the end food or drink product.
54. A method according to claim 51, wherein the food or drink product is selected from the group consisting of: a soup, a pasta sauce, a cereal bar, a. milkshake pre-mix, a breakfast cereal and a sports drink.
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
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GB1217057.7 | 2012-09-22 | ||
GBGB1217057.7A GB201217057D0 (en) | 2012-09-22 | 2012-09-22 | Low caloric methods, compositons and substances for increasing fatty oxidation in humans and or animal bodies |
GBGB1217163.3A GB201217163D0 (en) | 2012-09-26 | 2012-09-26 | A low caloric dietary composition and mehtod for improving body composition, muscular stength and activating fatty oxidation in skeletal muscle, |
GB1217163.3 | 2012-09-26 | ||
GB1217582.4 | 2012-10-02 | ||
GBGB1217582.4A GB201217582D0 (en) | 2012-10-02 | 2012-10-02 | A dietry composition and method for improving performance by attentuating competition between carbohydrate and fat oxidation to delay the onset of fatigue |
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