JP2020031556A - Muscle damage inhibitor - Google Patents

Abstract

To provide a muscle damage inhibitor capable of inhibiting muscle from being damaged during exercise.SOLUTION: A muscle damage inhibitor includes imidazole dipeptide and branched amino acid; a content ratio of the branched amino acid to the imidazole dipeptide is, for example, 0.2 or more and 0.6 or less based on weight.SELECTED DRAWING: Figure 4

Description

  The present invention relates to a muscle damage inhibitor.

  As an anti-fatigue component, a branched-chain amino acid, imidazole dipeptide, and the like are known. It is stated that in order to obtain an anti-fatigue effect by these, it is necessary to take at least 2000 mg for a branched-chain amino acid and at least 400 mg for an imidazole dipeptide. Further, an anti-fatigue agent composition containing a branched-chain amino acid and an imidazole dipeptide is known (for example, see Patent Document 1).

  In exercise involving eccentric muscle contraction, active oxygen generated during exercise causes minute damage to muscles, and delayed muscle pain develops based on the damage. Such muscle damage and delayed muscle pain cause a decrease in maximal muscle strength and range of motion, and affect many motor functions such as muscle fatigue, submaximal muscle contraction, force exertion sensation, and motor learning. It is said to exert. In this connection, it is known that chicken breast extract containing imidazole dipeptide reduces delayed myalgia (see, for example, Non-Patent Document 1).

JP 2014-114244 A

Pan Pacific University research bulletin (1), 83-87, 2008

  An object of the present invention is to provide a muscle damage inhibitor capable of suppressing muscle damage during exercise.

  A first aspect of the present invention is a muscle damage inhibitor comprising an imidazole dipeptide and a branched-chain amino acid. The content ratio of the branched-chain amino acid to the imidazole dipeptide in the muscle damage inhibitor is, for example, from 0.2 to 0.6 on a weight basis. Further, the muscle damage inhibitor may further include arginine, citric acid and coenzyme Q10. A second aspect is a method for suppressing muscle damage, which comprises ingesting the muscle damage inhibitor into a subject. In the method for suppressing muscle damage, the muscle damage inhibitor may be taken before exercise.

  According to the present invention, a muscle damage inhibitor capable of suppressing muscle damage during exercise can be provided.

It is a graph which shows the average power at the time of an exercise load. It is a graph which shows the change of the oxidative stress degree after an exercise load. It is a graph which shows the change of the antioxidant power after an exercise load. It is a graph which shows 8-OHdG production rate after exercise load. It is a graph which shows the change of the blood lactate concentration after exercise load. It is a graph which shows the increase amount of the blood lactate concentration until 3 minutes after exercise load. It is a graph which shows the change of the fatigue feeling VAS after an exercise load. It is a graph which shows the change of myalgia VAS at the time of lower leg flexion after exercise load. It is a graph which shows the change of myalgia VAS at the time of lower limb extension after exercise load.

  In this specification, the term "step" is included not only in an independent step but also in the case where the intended purpose of the step is achieved even if it cannot be clearly distinguished from other steps. . Further, the content of each component in the composition means the total amount of the plurality of substances present in the composition, unless otherwise specified, when there are a plurality of substances corresponding to each component in the composition. Hereinafter, embodiments of the present invention will be described in detail. However, the embodiments described below exemplify a muscle damage inhibitor for embodying the technical idea of the present invention, and the present invention is not limited to the muscle damage inhibitor shown below. Further, suppression of muscle damage means suppression of oxidative damage to muscles caused by active oxygen generated by exercise involving eccentric muscle contraction.

  The muscle damage inhibitor comprises an imidazole dipeptide as a first component and a branched chain amino acid as a second component as active ingredients. By including a branched-chain amino acid in addition to the imidazole dipeptide, it is possible to effectively suppress muscle damage during exercise with a smaller amount of intake than when each is taken alone. In addition, since muscle damage during exercise is suppressed, delayed muscle pain is suppressed, and exercise performance on and after the next day can be maintained and improved. Further, the muscle damage inhibitor has an anti-fatigue effect, and can exhibit an excellent effect of reducing and recovering fatigue after exercise.

  The effect of suppressing muscle damage due to exercise can be evaluated, for example, by measuring the amount of 8-hydroxydeoxyguanosine (hereinafter may be abbreviated as 8-OHdG) in urine after exercise. 8-OHdG is known as a DNA oxidative damage marker in vivo, and it is known that the amount of 8-OHdG in urine increases after strenuous exercise. Therefore, if the increase in urinary 8-OHdG amount after exercise is suppressed, it indicates that muscle damage during exercise is suppressed.

  The imidazole dipeptide as the first component is a dipeptide formed from L-histidine and β-alanine or a derivative thereof. Examples of the imidazole dipeptide include, for example, L-carnosine, L-anserin, L-valenin, L-homocarnosine, carcinine, and their acyl derivatives (eg, N-acetyl-L-carnosine, N-acetyl-L-anserin, -Acetyl-L-homocarnosine), and at least one member selected from the group consisting of these is preferable, and at least one member selected from the group consisting of L-carnosine, L-anserine and L-valenin is preferable. More preferably, L-carnosine is particularly preferred. In addition, the acyl derivative of the imidazole dipeptide can be produced by a method known per se using, for example, a known acylating agent.

  The imidazole dipeptide may be contained in the muscle damage inhibitor as a free base or as a salt. Salts include inorganic salts such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate; acetate, maleate, fumarate, tartrate, succinate, citric acid Organic salts such as salt, lactate, methanesulfonate, p-toluenesulfonate, salicylate, oxalate, stearate, ascorbate, malate, adipate, gluconate, etc. No.

  Imidazole dipeptide is a dipeptide component abundantly found in vertebrate muscle, brain and the like. It is an anti-fatigue component that is abundantly present in muscles of migratory birds, migratory fish and the like, and is capable of keeping these animals active for a long time. It is generally known that, in order to obtain an excellent anti-fatigue effect using imidazole dipeptide alone, it is necessary to take 400 mg or more (for example, “Pharmacology and Treatment”, pp. 119-212, vol. 36, No. 3, 2008 and pp 255-263, vol. 37, No. 3, 2009). The imidazole dipeptide can be obtained as an extract obtained by a method such as hot water extraction, solvent extraction, or supercritical extraction from animal materials such as livestock meat including fish and shellfish, chicken meat, and the like, and a purified product thereof. As the imidazole dipeptide, a commercially available pure product may be used, and chemically synthesized L-carnosine is preferably used.

  The content of the imidazole dipeptide in the muscle damage inhibitor is, for example, 5% by weight to 80% by weight, preferably 10% by weight to 50% by weight, or 10% by weight to 40% by weight. The content of imidazole dipeptide in the muscle damage inhibitor is a content of imidazole dipeptide as a daily intake of, for example, 50 mg or more and 1000 mg or less, preferably 80 mg or more and 800 mg or less, 100 mg or more and less than 400 mg, or The content is 100 mg or more and 300 mg or less.

  Branched chain amino acid (BCAA) as the second component is a general term for valine, leucine and isoleucine, and is an essential amino acid that cannot be synthesized in the human body. In addition, branched-chain amino acids are important nutrients that provide energy for muscle. Although branched-chain amino acids are known to have an anti-fatigue effect, at least 2,000 mg is required to achieve the anti-fatigue effect. The muscle damage inhibitor preferably contains at least one selected from the group consisting of valine, leucine and isoleucine as a branched amino acid, and more preferably contains at least leucine as an essential component.

  The content ratio of the branched-chain amino acid to the imidazole dipeptide in the muscle damage inhibitor is, for example, 0.2 to 0.6, and preferably 0.3 to 0.5 on a weight basis. The content of the branched-chain amino acid in the muscle damage inhibitor is, for example, 1% by weight to 25% by weight, preferably 3% by weight to 20% by weight, or 5% by weight to 15% by weight. . The content of the branched-chain amino acid in the muscle damage inhibitor is, for example, a content of 10 mg or more and 200 mg or less as a daily intake of the branched-chain amino acid, preferably 40 mg or more and 150 mg or less, and 40 mg or more and 100 mg or less. Or the content is 60 mg or more and 100 mg or less.

  When the muscle damage inhibitor contains at least one of valine and isoleucine other than leucine as a branched-chain amino acid, the content ratio of at least one of valine and isoleucine to imidazole dipeptide is, for example, 0.6 or less on a weight basis, preferably Is 0.4 or less, 0.2 or less, or 0.1 or less. The lower limit is, for example, 0.01 or more.

  The muscle damage inhibitor may further include at least one third component selected from the group consisting of arginine, citrulline, carnitine, folic acid, glycerophosphocholine, and hydroxymethylbutyric acid. When the muscle damage inhibitor contains the third component, the content ratio of the third component to the imidazole dipeptide is, for example, from 0.2 to 0.6, preferably from 0.3 to 0.5 on a weight basis. is there. The content of the third component in the muscle damage inhibitor is, for example, 1% by weight or more and 25% by weight or less, preferably 3% by weight or more and 20% by weight or less, or 5% by weight or more and 15% by weight or less. .

  The muscle damage inhibitor may further include at least one fourth component selected from the group consisting of coenzyme Q10 (which may be reduced coenzyme Q10) and pyrroloquinoline quinone. When the muscle damage inhibitor comprises the fourth component, the content ratio of the fourth component to the imidazole dipeptide is, for example, 0.05 or more and 0.6 or less on a weight basis, preferably 0.1 or more and 0.4 or less, Or it is 0.1 or more and 0.2 or less. The content of the fourth component in the muscle damage inhibitor is, for example, 1% by weight to 15% by weight, preferably 2% by weight to 10% by weight, or 2% by weight to 5% by weight. .

  The muscle damage inhibitor may further include at least one fifth component selected from the group consisting of citric acid, tartaric acid, ascorbic acid, malic acid, lactic acid, and gluconic acid. When the muscle damage inhibitor comprises the fifth component, the content ratio of the fifth component to the imidazole dipeptide is, for example, 0.2 or more and 0.6 or less, preferably 0.3 or more and 0.5 or less on a weight basis. is there. The content of the fifth component in the muscle damage inhibitor is, for example, 1% by weight to 25% by weight, preferably 3% by weight to 15% by weight, or 5% by weight to 15% by weight. .

  It is also preferable that the muscle damage inhibitor comprises at least arginine, coenzyme Q10 and citric acid in addition to the imidazole dipeptide and the branched-chain amino acid.

  The dosage form of the muscle damage inhibitor can be appropriately selected according to the purpose of use and the like. Examples of the dosage form include oral administration preparations such as tablets, capsules, granules, troches, powders, and liquids; and parenteral administration preparations such as injections, drops, and suppositories. These preparations can be manufactured according to a known method using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, diluents and the like.

  Excipients include, for example, lactose, sucrose, glucose, mannitol, sorbitol, corn starch, potato starch, crystalline cellulose, acacia, dextran, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, calcium carbonate, calcium hydrogen phosphate, etc. Can be mentioned. Examples of the lubricant include stearic acid, calcium stearate, magnesium stearate, talc, colloidal silica and the like. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol and the like. Examples of the disintegrant include low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch, sodium carboxymethylstarch, and crosslinked polyvinylpyrrolidone. Examples of the stabilizer include methyl paraben, propyl paraben, benzyl alcohol and the like. The flavoring agent is appropriately selected from, for example, commonly used sweeteners, sour agents, flavors and the like.

  The muscle damage inhibitor can also be constituted as a food composition such as a health food and a health supplement, a beverage composition and the like. Examples of the form of the food composition, the beverage composition and the like include fermented milk, tea beverage, processed juice beverage, nutritional drink, sports drink, cookie, candy, tablet and the like. In particular, sports drinks and energy drinks are preferably used as beverage compositions having various physiological effects. By configuring it as a sports drink or the like, muscle damage during exercise can be effectively suppressed simultaneously with hydration.

  When the muscle damage inhibitor is constituted as a beverage composition such as a sports drink and an energy drink, the daily intake of imidazole dipeptide is, for example, 50 mg or more and 1000 mg or less, preferably 80 mg or more and 800 mg or less, 100 mg or more and less than 400 mg, Alternatively, it can be configured to be 100 mg or more and 300 mg or less. The daily intake of the branched-chain amino acid can be, for example, 10 mg or more and 100 mg or less, preferably 20 mg or more and 80 mg or less, 20 mg or more and 60 mg or less, or 30 mg or more and 50 mg or less. At this time, the content ratio of the branched-chain amino acid to the imidazole dipeptide in the beverage composition is, for example, from 0.2 to 0.6, and preferably from 0.3 to 0.5 on a weight basis. When a beverage composition, 500 mL or 500 g container, 350 mL or 350 g container, 200 mL container or 200 g container, 100 mL or 100 g container, or 50 mL or 50 g container when adding the intake per serving, Efficient intake is possible in a short time.

In producing the food and drink composition, other food materials, that is, various sugars, emulsifiers, thickeners, sweeteners, acidulants, flavors, amino acids, fruit juices, and the like can be appropriately added. Specifically, sugars such as sucrose, isomerized sugar, glucose, fructose, palatinose, trehalose, lactose, xylose; sorbitol, xylitol, erythritol, lactitol, palatinit, sugar alcohols such as reduced starch syrup, reduced maltose syrup; aspartame, Sweeteners such as stevia, acesulfame potassium, sucralose and the like; emulsifiers such as sucrose fatty acid ester, glycerin fatty acid ester, lecithin; thickening (stabilizing) agents such as carrageenan, xanthan gum, guar gum, pectin, locust bean gum; Lactic acid, malic acid and other acidulants; at least one selected from lemon juice, orange juice, fruit juices such as berry juice and the like can be appropriately added. In addition, vitamins such as vitamin A, vitamin B, vitamin C, vitamin D and vitamin E; and minerals such as calcium, iron, manganese and zinc may be added.

Method for suppressing muscle damage The method for suppressing muscle damage includes administering the muscle damage inhibitor to a subject. Preferably, the muscle damage inhibitor is administered to the subject before the subject exercises, especially strenuous exercise. The subject of the administration is, for example, a mammal including a human. The total daily dose is appropriately selected depending on the subject to be administered, the purpose, and the like, and is, for example, 50 mg or more and 1000 mg or less, preferably 100 mg or more and 400 mg or less as imidazole dipeptide. The branched chain amino acid is, for example, 10 mg or more and 200 mg or less, preferably 60 mg or more and 100 mg or less.

  Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.

(Example 1)
Carnosine main component supplement containing L-carnosine: 200 mg, leucine: 80 mg, arginine: 80 mg, citric acid: 80 mg, and coenzyme Q10: 30 mg in 4 capsules (hereinafter abbreviated as CAR; manufactured by Hamari Pharmaceutical Co., Ltd.) ) And placebo (hereinafter sometimes abbreviated as PLA) containing starch in a capsule were prepared as test agents. Nine healthy adult men (20 to 22 years old) were selected as test subjects, the purpose and method of the experiment were explained in detail, and written consent was obtained.

Experimental Procedures The experimental design was a double-blind, randomized crossover method with a washout period of 7 days or more. The breakfast on the day of the experiment was a regular meal, avoiding foods with strong antioxidant effects. From the morning of the experiment to the end of the experiment, drinking water was allowed. After arriving at the laboratory, the test subjects were kept in a resting state for at least 20 minutes, blood samples were taken at rest, and control food was taken. Immediately after eating, CAR (4 capsules) or PLA was orally ingested together with water. Exercise load was started 2 hours after ingestion. In addition, blood collection and urination before exercise were performed 30 minutes before exercise. Blood was collected at 3 and 30 minutes after the end of the exercise, and blood and urine were collected at 2 hours.

Exercise load In the exercise, three full-cycle exercises for 30 seconds were performed according to the method of a wingate anaerobic test (anoxic endurance test). The recovery time during exercise was 4 minutes. Bicycle exercise was performed using a bicycle ergometer (Powermax-VII, manufactured by Combi Corporation) at a load of 0.075 kp per kg of body weight. The height of the saddle and handle was adjusted for each subject, and both feet were fixed to the pedals with toe clips. He instructed him to stay up from the saddle while exercising and always pedal with maximum effort. Exercise performance was evaluated from the average power during exercise. Before the exercise, a warm-up for about 10 minutes including stretching around the lower limbs and full-stroke biking exercise for 5 seconds was performed. Table 1 and FIG. 1 show the average power (W), the peak power (W), and the average value (W) of the three average powers during exercise.

Exercise load

  As shown in Table 1 and FIG. 1, there was no significant difference in exercise performance between the carnosine-based supplement and the placebo.

Measurement items In the following measurement items, the average value and the standard deviation of the measured numerical values are shown. The test for the difference between the mean values of the time series variation of the blood data was performed by one-way analysis with repetition. The test of the difference of other average values was performed by t test (t-test).

1. Oxidative stress level (d-ROMs) and antioxidant power (BAP)
BAP and d-ROMs in blood were measured using a free radical analyzer (FREE Carrio Duo, manufactured by Wismer Inc.). BAP was evaluated based on the reducing action of reducing ferric iron in the plasma to ferric iron. d-ROMs were evaluated by measuring plasma levels of hydroperoxide, a metabolite due to free radicals. The blood collection method was performed using a micro bed with a fingertip self blood collection method. The results of the degree of oxidative stress (d-ROMs) are shown in Table 2 and FIG. 2, and the results of the antioxidant power (BAP) are shown in Table 3 and FIG.

Oxidative stress level (d-ROMs)

Antioxidant power (BAP)

The d-ROMs showed a significant increase at 3 minutes after exercise for both the carnosine-based supplement and the placebo, but no significant difference was observed between the two conditions.
BAP did not change significantly from the rest in both conditions. In addition, BAP under the carnosine main component supplement intake condition showed a significantly (p <0.05) lower value 3 minutes after exercise than the placebo intake condition.

2. 8-OHdG in urine
For urinary 8-hydroxydeoxyguanosine (8-OHdG), the urinary 8-OHdG concentration was measured 2 hours after exercise using a urinary oxidative stress marker measurement system (manufactured by Celista Corporation). For the obtained urinary 8-OHdG concentration, a production rate per unit time (ng / h / kg) was calculated from the elapsed time from urination and the amount of urination. The urinary 8-OHdG generation rate was corrected for body weight. The results are shown in Table 4 and FIG.

8-OHdG in urine

  The urinary 8-OHdG production rate was significantly (p <0.05) lower in the carnosine-based supplement intake condition than in the placebo intake condition.

3. Blood lactate concentration Blood lactate concentration (mmol / L) was measured using Lactate Pro 2 (Arkray, Inc.). The measurement was performed four times in total at rest, 3 minutes, 30 minutes, and 2 hours after the end of the exercise. The results of the blood lactate concentration (mmol / L) are shown in Table 5 and FIG. Table 5 also shows the increase (mmol / L) from resting to 3 minutes after exercise, and the graph is shown in FIG.

Blood lactate concentration

  Blood lactate concentration after exercise did not differ significantly between the two conditions. On the other hand, the mean value of the increase in blood lactate concentration from resting to 3 minutes after exercise was low (p = 0.06), although the carnosine-based supplement intake condition was not significant compared to the placebo intake condition. showed that.

4. Fatigue VAS Test and Lower Limb Muscle Pain VAS Test Fatigue was measured using a fatigue VAS test sheet indicated by the Japan Fatigue Society. VAS for lower limb myalgia evaluated two types of myalgia: extension and flexion of the leg. The muscle pain was evaluated on the left side of a 10 cm straight line as "no muscle pain when bending the right leg in a standing position" or "no muscle pain when stretching the right leg in a standing position" And, on the right side, "I feel the greatest muscle pain that I have never experienced when bending my right leg in a standing position" or "What I have experienced when stretching my right leg in a standing position" I feel the greatest muscle pain without it. " The fatigue VAS test and the lower limb myalgia VAS test were performed four times in total at rest, 3 minutes, 30 minutes, and 2 hours after the end of exercise. The results of the fatigue VAS test are shown in Tables 6 and 7, the results of the muscle pain VAS test for lower limb flexion are shown in Tables 7 and 8, and the results of the muscle pain VAS test for lower limb extension are shown in Tables 8 and 9.

VAS test for fatigue

VAS test for muscle pain during lower leg flexion

VAS test for muscle pain during lower limb extension

  The fatigue VAS at 2 hours after the exercise showed a significantly (p <0.01) lower value in the carnosine-based supplement intake condition than in the placebo intake condition. On the other hand, there was no significant difference between the two conditions in the VAS for lower limb myalgia.

(Example 2)
As test agents, carnosine main component supplement 2 containing 200 mg of L-carnosine and 80 mg of leucine (CAR2; manufactured by Hamari Pharmaceutical Co., Ltd.) and a placebo (PLA) in which starch was encapsulated were prepared. The effect of supplement 2 was examined in the same manner as in 1.

Exercise load

Oxidative stress level (d-ROMs)

Antioxidant power (BAP)

8-OHdG in urine

Blood lactate concentration

VAS test for fatigue

VAS test for muscle pain during lower leg flexion

VAS test for muscle pain during lower limb extension

  The supplement containing L-carnosine and leucine showed the same effect as the supplement of Example 1.

Claims (3)

  A muscle damage inhibitor comprising an imidazole dipeptide and a branched-chain amino acid.   The muscle damage inhibitor according to claim 1, wherein the content ratio of the branched-chain amino acid to the imidazole dipeptide is from 0.2 to 0.6 on a weight basis.   The muscle damage inhibitor according to claim 1 or 2, further comprising arginine, citric acid and coenzyme Q10.