EP4734992A1 - Methods and compositions comprising trigonelline for treating muscle decline and a kidney dysfunction - Google Patents

Abstract

The present disclosure generally relates to methods and compositions comprising trigonelline that treat or prevent a disease or condition associated with muscle decline and/or a kidney dysfunction. Moreover, methods and compositions comprising trigonelline for decelerate glomerular filtration rate (GFR) progression and/or decrease glomerular hyalinosis damage and/or to improve the lean mass of a muscle. In addition, methods and compositions comprising trigonelline to improve the lean mass of a muscle and/or to improve the muscle fiber size are disclosed. Also disclosed are methods and compositions comprising trigonelline to improve the level of at least one nicotinamide adenine dinucleotide. Also disclosed are methods and compositions comprising trigonelline to increase muscle stem cells and/or mitigate a decline of muscle stem cells.

Description

METHODS AND COMPOSITIONS COMPRISING TRIGONELLINE FOR TREATING MUSCLE DECLINE AND A KIDNEY DYSFUNCTION

[0001] This application claims priority to U.S. provisional patent application no. 63/523,960 filed June 29, 2023, the entire contents of which are incorporated by reference.

[0002] The present disclosure generally relates to methods and compositions comprising trigonelline that treat or prevent a disease or condition associated with muscle decline and/or a kidney dysfunction. Moreover, methods and compositions comprising trigonelline for decelerate glomerular filtration rate (GFR) progression and/or decrease glomerular hyalinosis damage and/or to improve the lean mass of a muscle. In addition, methods and compositions comprising trigonelline to improve the lean mass of a muscle and/or to improve the muscle fiber size are disclosed. Also disclosed are methods and compositions comprising trigonelline to improve the level of at least one nicotinamide adenine dinucleotide.

BACKGROUND

[0003] The loss of muscle mass that occurs during muscle wasting may be characterized by muscle protein degradation due to catabolism. Muscle protein catabolism, whether caused by a high degree of protein degradation or a low degree of protein synthesis, leads to a decrease in muscle mass and to muscle wasting.

[0004] Muscle decline in form of muscle wasting is associated with chronic, neurological, genetic or infectious pathologies, diseases, illnesses or conditions. In particular muscle decline is related to chronic kidney disease (CKD), end stage renal failure (ESRD), metabolic dysfunction-induced muscle wasting, dialysis, diabetes, muscle loss and/or kidney failure due to hospitalization in the intensive care unit, Pompe disease, metabolic acidosis, methylmalonic aciduria, disuse atrophy, protein-energy wasting amongst others.

[0005] Muscle wasting is a common complication of CKD, characterized by the loss of muscle mass, strength and function, which significantly increases the risk of morbidity and mortality in this population. Numerous complications associated with declining renal function and lifestyle activate catabolic pathways and impair muscle regeneration, resulting in substantial protein wasting. [0006] CKD is a gradual and progressive loss of the ability of the kidneys to excrete wastes, concentrate urine, reabsorb proteins and amino acids, and conserve electrolytes. Unlike acute kidney failure with its abrupt but reversible of kidney function, the kidney functions in chronic kidney disease progress and deteriorate irreversibly towards end stage renal disease (ESRD). CKD arises from many heterogeneous disease pathways that alter the function and structure of the kidney irreversibly, over months or years.

[0007] Diabetes and hypertension are the main causes of CKD in all high-income and middleincome countries, and also in many low-income countries. Incidence, prevalence, and progression of CKD also vary within countries by ethnicity and social determinants of health, possibly through epigenetic influence. Many people are asymptomatic or have non-specific symptoms such as lethargy, itch, or loss of appetite. Diagnosis is commonly made after chance findings from screening tests such as urinary dipstick or blood tests, or when symptoms become severe. The best available indicator of overall kidney function is the glomerular filtration rate (GFR). Disease and management are classified according to stages of disease severity, which are assessed from GFR and albuminuria, and clinical diagnosis (cause and pathology). Presence of proteinuria is associated with increased risk of progression of CKD. The diagnosis of CKD rests on establishing a chronic reduction in kidney function and structural kidney damage.

[0008] CKD is diagnosed using a staging system that demonstrates the amount of kidney function available (stage 1 = normal kidney function) and patients often do not present symptoms in the early stages. Stage 5 of CKD is ESRD, which is a complete or near complete failure of the kidneys and usually occurs when kidney function is less than 10% of baseline.

SUMMARY OF THE INVENTION

[0009] In a first aspect, the present disclosure provides a method of treating and/or preventing a disease or condition associated with muscle decline and/or a kidney dysfunction. The method comprises administering to a subject in need thereof an effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof. In one embodiment the muscle decline and/ or the kidney dysfunction is treated and/ or prevented in an early stage of chronic kidney disease and/ or a late stage of chronic kidney disease. [ooio] In another aspect, the present disclosure provides a method for decelerating glomerular filtration rate (GFR) progression in a subject in need thereof. The method comprises administering to the subject in need thereof an effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, the present disclosure provides a method for decreasing glomerular hyalinosis damage in a subject in need thereof. The method comprises administering to the subject in need thereof an effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof.

[0012] In another aspect, the present disclosure provides a method for improving the lean mass of a muscle in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments of the aforementioned aspects, the muscle is tibialis anterior and/or extensor digitorum longus (EDL), and/or soleus muscle.

[0014] In another aspect, the present disclosure provides a method for improving the muscle fiber size in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof.

[0015] In another aspect, the present disclosure provides a method for improving the level of at least one nicotinamide adenine dinucleotide in a muscle of a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments of the aforementioned aspects, the subject has a disease or condition selected from chronic kidney disease, metabolic induced muscle wasting, end-stage renal disease, dialysis, diabetes, muscle loss and/ or kidney failure due to hospitalization in the intensive care unit, Pompe disease, metabolic acidosis, methylmalonic aciduria, disuse atrophy, protein-energy wasting and combinations thereof. [0017] In other embodiments, the composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof is administered enterally.

[0018] In further embodiments, the composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof is administered parenterally.

[0019] In some embodiments, the trigonelline is micronized.

[0020] In another aspect, the present disclosure provides a nutritional composition for use in treating and/ or preventing a disease or condition associated with muscle decline and/or a kidney dysfunction. The nutritional composition comprises a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof. Preferably the nutritional composition contains an amount of trigonelline effective for treating and/or preventing a disease or condition associated with muscle decline and/or a kidney dysfunction in a subject in need thereof.

[0021] In one embodiment, the composition is selected from the group consisting of a food product, a food for special medical purposes (FSMP), a nutritional supplement, a dairy-based drink, a low-volume liquid supplement, a meal replacement beverage and combinations thereof.

[0022] In another embodiment, the composition is formulated for oral administration.

[0023] In another aspect, the present disclosure provides a unit dosage form for use in a method of treating and/or preventing a disease or condition associated with muscle decline and/ or a kidney dysfunction. The unit dosage form comprises a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof. Preferably, the unit dosage form contains an amount of trigonelline effective for treating and/or preventing a disease or condition associated with muscle decline and/or a kidney dysfunction in a subject in need thereof.

[0024] In one embodiment, the unit dosage form is selected from the group consisting of a food product, a food for special medical purposes (FSMP), a nutritional supplement, a dairy-based drink, a low-volume liquid supplement, a meal replacement beverage and combinations thereof.

[0025] In another embodiment, the unit dosage form is formulated for enteral administration. [0026] In some embodiments, the composition and/or the unit dosage form contains an amount of trigonelline effective to decelerate glomerular filtration rate (GFR) progression and/or decrease glomerular hyalinosis damage and/or to improve the lean mass of a muscle.

[0027] In other embodiments, the amount of the composition comprising trigonelline or the trigonelline or a pharmaceutically acceptable salt thereof is effective to improve the lean mass of a muscle and/ or to improve the muscle fiber size.

[0028] In other embodiments, the muscle is tibialis anterior and/or extensor digitorum longus (EDL), and/or soleus muscle.

[0029] In another aspect, the present disclosure provides a method of increasing muscle stem cells and/or mitigating a decline of muscle stem cells, in a subject having diabetes, the method comprising administering to the subject having diabetes an effective amount of trigonelline or a pharmaceutically acceptable salt thereof. The muscle maybe tibialis anterior and/or extensor digitorum longus (EDL), and/or soleus muscle. Preferably the trigonelline or pharmaceutically acceptable salt thereof is administered enterally or parenterally. The trigonelline or pharmaceutically acceptable salt thereof may be administered in a composition selected from the group consisting of a food product, a food for special medical purposes (FSMP), a nutritional supplement, a dairy-based drink, a low-volume liquid supplement, a meal replacement beverage, and combinations thereof. Preferably the trigonelline or pharmaceutically acceptable salt thereof is micronized.

[0030] An advantage of one or more aspects and embodiments provided by the present disclosure is to help maintain healthy muscle mass.

[0031] Another advantage of one or more aspects and embodiments provided by the present disclosure is to help stabilizing a kidney dysfunction.

[0032] Yet another advantage of one or more aspects and embodiments provided by the present disclosure is to help ameliorating kidney function.

[0033] An advantage of one or more aspects and embodiments provided by the present disclosure is to help improving the lean mass of a muscle. [00341 Another advantage of one or more aspects and embodiments provided by the present disclosure is to help decelerate glomerular filtration rate (GFR) progression.

[0035] Yet another advantage of one or more aspects and embodiments provided by the present disclosure is to help decreasing glomerular hyalinosis damage.

[0036] An advantage of one or more aspects and embodiments provided by the present disclosure is to improve the endurance and/or efficiency of a muscle.

[0037] Another advantage of one or more aspects and embodiments provided by the present disclosure is to improve the muscle fiber size.

[0038] An advantage of one or more aspects and embodiments provided by the present disclosure is to reduce muscle atrophy.

[0039] Another advantage of one or more aspects and embodiments provided by the present disclosure is to increase the muscle bioenergetics nucleotides and nucleotides important for cellular signaling.

[0040] Additional features and advantages are described herein and will be apparent from the following Figures and Detailed Description.

BRIEF DESCRIPTION OF THE FIGURES

[0041] FIG. 1 shows lean mass measured in mice at 8 weeks of treatment (endpoint) with trigonelline, dosed at 300 mg/kg/day (+TG, db/db+trigonelline group) compared to a vehicle group (Diabetic, db/db+V group), control group (Control, db/m+V group) and dapa group (dapa, db/db+dapa group). Lean mass was measured using an EchoMRI.

[0042] FIG. 2a shows the muscle mass of the tibialis anterior in grams measured in mice after 8 weeks treatment with trigonelline, dosed at 300 mg/kg/day (+TG, db/db+trigonelline group) compared to a vehicle group (Diabetic, db/db+V group), control group (Control, db/m+V group) and dapa group (dapa, db/db+dapa group). The muscle mass of the tibialis anterior was measured by weighing on a precision scale. [0043] FIG. 2b shows the muscle mass of extensor digitorum longus (EDL) in grams measured in mice after 8 weeks treatment with trigonelline, dosed at 300 mg/kg/day (+TG, db/db+trigonelline group) compared to a vehicle group (Diabetic, db/db+V group), control group (Control, db/m+V group) and dapa group (dapa, db/db+dapa group). The muscle mass of the tibialis anterior was measured by weighing on a precision scale.

[0044] FIG. 2c shows the muscle mass of soleus in grams measured in mice after 8 weeks treatment with trigonelline, dosed at 300 mg/kg/day (+TG, db/db+trigonelline group) compared to a vehicle group (Diabetic, db/db+V group), control group (Control, db/m+V group) and dapa group (dapa, db/db+dapa group). The muscle mass of the tibialis anterior was measured by weighing on a precision scale.

[0045] FIG. 3 shows fiber size distribution measured by immunofluorescence in mice after 8 weeks treatment with trigonelline, dosed at 300 mg/kg/day (+TG, db/db+trigonelline group) compared to a vehicle group (Diabetic, db/db+V group), control group (Control, db/m+V group) and dapa group (dapa, db/db+dapa group). The fiber size distribution was measured by an automated image processing algorithm.

[0046] FIG. 4 shows the number of fiber measured by immunofluorescence in mice after 8 weeks treatment with trigonelline, dosed at 300 mg/kg/ day (+TG, db/db+trigonelline group) compared to a vehicle group (Diabetic, db/db+V group), control group (Control, db/m+V group) and dapa group (dapa, db/db+dapa group). The fiber size distribution was measured by an automated image processing algorithm.

[0047] FIG. 5 shows delta glomerular filtration rate measured in mice between 4 weeks (Midpoint) and 8 weeks (endpoint) treatment with trigonelline, dosed at 3oomg/kg/day (+TG, db/db+trigonelline group) compared to a vehicle group (Diabetic, db/db+V group), control group (Control, db/m+V group) and dapa group (dapa, db/db+dapa group). Glomerular filtration rate was measured using a transdermal GFR monitor device after an intravenous injection of FITC-Sinistrin (50 mg/kg).

[0048] FIG. 6 shows glomerular hyalinosis damage measured in mice after 8 weeks (Endpoint) treatment with trigonelline, dosed at 300mg/kg/day (+TG, db/db+trigonelline group) compared to a vehicle group (Diabetic, db/db+V group), control group (Control, db/m+V group) and dapa group (dapa, db/db+dapa group). Glomerular hyalinosis damage was determined using a periodic acid Schiff hematoxylin staining.

[0049] FIG. 7 shows NAD+ level in kidney measured in mice after 8 weeks treatment with trigonelline, dosed at 300 mg/kg/day (+trigonelline, db/db+trigonelline group) compared to a vehicle group (Diabetic, db/db+V group) and a control group (Healthy, db/m+V group). The kidney NAD+ level was measured using a NAD/NADH kit.

[0050] FIG. 8 is a graph showing experimental results from Example 2 disclosed herein.

DETAILED DESCRIPTION

DEFINITIONS

[0051] Some definitions are provided hereafter. Nevertheless, definitions may be located in the “Embodiments” section below, and the above header “Definitions” does not mean that such disclosures in the “Embodiments” section are not definitions.

[0052] All percentages expressed herein are by weight of the total weight of the composition unless expressed otherwise. As used herein, “about,” “approximately” and “substantially” are understood to refer to numbers in a range of numerals, for example the range of -10% to +10% of the referenced number, preferably -5% to +5% of the referenced number, more preferably -1% to +1% of the referenced number, most preferably -0.1% to +0.1% of the referenced number. All numerical ranges herein should be understood to include all integers, whole or fractions, within the range. Moreover, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 1 to 8, from 3 to 7, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.

[0053] As used in this disclosure and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a component” or “the component” includes two or more components.

[0054] The words “comprise,” “comprises” and “comprising” are to be interpreted inclusively rather than exclusively. Likewise, the terms “include,” “including” and “or” should all be construed to be inclusive, unless such a construction is clearly prohibited from the context. Nevertheless, the compositions disclosed herein may lack any element that is not specifically disclosed herein. Thus, a disclosure of an embodiment using the term “comprising” includes a disclosure of embodiments “consisting essentially of’ and “consisting of’ the components identified. A composition or dosage unit “consisting essentially of’ contains at least 50 wt.% of the referenced components, preferably at least 75 wt.% of the referenced components, more preferably at least 85 wt.% of the referenced components, most preferably at least 95 wt.% of the referenced components.

[0055] [0063] The term “and/or” used in the context of “X and/or Y” should be interpreted as “X,” or “Y,” or “X and Y.” Similarly, “at least one of X or Y” should be interpreted as “X,” or “Y,” or “X and Y.” For example, “muscle decline and/or a kidney dysfunction” should be interpreted as “muscle decline” or “a kidney dysfunction” or “both muscle decline and a kidney dysfunction”.

[0056] Where used herein, the terms “example” and “such as,” particularly when followed by a listing of terms, are merely exemplary and illustrative and should not be deemed to be exclusive or comprehensive. As used herein, a condition “associated with” or “linked with” another condition means the conditions occur concurrently, preferably means that the conditions are caused by the same underlying condition, and most preferably means that one of the identified conditions is caused by the other identified condition.

[0057] “Prevention” includes reduction of risk and/ or severity of a condition or disorder. The terms “treatment,” “treat” and “to alleviate” include both prophylactic or preventive treatment (that prevent and/or slow the development of a targeted pathologic condition or disorder) and curative, therapeutic or disease-modifying treatment, including therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder; and treatment of patients at risk of contracting a disease or suspected to have contracted a disease, as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition. The term does not necessarily imply that a subject is treated until total recovery. The terms “treatment” and “treat” also refer to the maintenance and/or promotion of health in an individual not suffering from a disease but who may be susceptible to the development of an unhealthy condition. The terms “treatment,” “treat” and “to alleviate” are also intended to include the potentiation or otherwise enhancement of one or more primary prophylactic or therapeutic measure. The terms “treatment,” “treat” and “to alleviate” are further intended to include the dietary management of a disease or condition or the dietary management for prophylaxis or prevention a disease or condition. A treatment can be patient- or doctor-related.

[0058] A "subject" or “individual” is a mammal, preferably a human. The term mammal may include but is not limited to a pet or a farm animal. In particular the term “farm animal” may include but is not limited to a horse (e.g., a pet or horse undergoing medical treatment), or cattle or poultry (e.g., cattle or poultry being used in agriculture). In particular the term “pet” may include but is not limited to senior pets (e.g., cats aged above 10 years or dogs aged above 7 years), pets with obesity, pets with diabetes and pets with CKD.

[0059] As used herein, an “effective amount” is an amount that prevents a deficiency, treats a disease or medical condition in an individual, or, more generally, reduces symptoms, manages progression of the disease, or provides a nutritional, physiological, or medical benefit to the individual. The relative terms “improved,” “increased,” “enhanced” and the like refer to the effects of the composition disclosed herein, namely a composition comprising urolithin or an urolithin or a pharmaceutically acceptable salt thereof.

[0060] The terms “food,” “food product” and “food composition” mean a product or composition that is intended for ingestion by an individual such as a human and provides at least one nutrient to the individual. A food product typically includes at least one of a protein, a lipid, a carbohydrate and optionally includes one or more vitamins and minerals. The compositions of the present disclosure, including the many embodiments described herein, can comprise, consist of, or consist essentially of the elements disclosed herein, as well as any additional or optional ingredients, components, or elements described herein or otherwise useful in a diet.

[0061] The term "unit dosage form", as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of the composition disclosed herein in an amount sufficient to produce the desired effect, in association with a pharmaceutically acceptable diluent, carrier or vehicle. The specifications for the unit dosage form depend on the particular compounds and/or compositions employed, the effect to be achieved, and the pharmacodynamics associated with each compound and/or composition in the host. [0062] “Chronic kidney disease (CKD)” encompasses the presence of kidney damage (i.e., albuminuria) or decreased kidney function (i.e., GFR <60 mL/min per 1.73 m²) for 3 months or more, irrespective of clinical diagnosis. CKD is classified into five stages on the basis of GFR: more than 90 mL/min per 1.73 m² (stage 1), 60-89 mL/min per 1.73 m² (stage 2), 30-59 mL/min per 1.73 m² (stage 3), 15-29 mL/min per 1.73 m² (stage 4), and less than 15 mL/min per 1.73 m² (stage 5).

[0063] “Early stage of chronic kidney disease” encompasses chronic kidney disease in stages 2 and 3 on the basis of GFR: 60-89 mL/min per 1.73 m² (stage 2), 30-59 mL/min per 1.73 m² (stage 3). Preferably, “early stage of chronic kidney disease” encompasses chronic kidney disease in stage 2 on the basis of GFR: 60-89 mL/min per 1.73 m².

[0064] “Late stage of chronic kidney disease” encompasses chronic kidney disease in stages 4 and 5 on the basis of GFR: 15-29 mL/min per 1.73 m² (stage 4), and less than 15 mL/min per 1.73 m² (stage 5). Preferably, “late stage of chronic kidney disease” encompasses chronic kidney disease in stage 4 on the basis of GFR: 15-29 mL/min per 1.73 m².

[0065] “End-stage renal disease (ESRD)” encompasses the condition of individuals with CKD, who require a kidney replacement therapy. Preferably, ESRD encompasses chronic kidney disease in stage 5 on the basis of GFR: less than 15 mL/min per 1.73 m².

[0066] “Metabolic induced muscle wasting” encompasses a prolonged catabolic state, where muscle protein breakdown exceeds the rate of protein synthesis.

[0067] "Diabetes" encompasses both the type I and type II forms of the disease. Non-limiting examples of risk factors for diabetes include: waistline of more than 40 inches for men or 35 inches for women, blood pressure of 130/85 mmHg or higher, triglycerides above 150 mg/dl, fasting blood glucose greater than 100 mg/dl or high-density lipoprotein of less than 40 mg/dl in men or 50 mg/dl in women.

[0068] “Pompe disease” encompasses the classic infantile form, non-classic infantile form, and late-onset form. In children with classic or non-classic infantile-onset Pompe disease, the activity of the acid alpha-glucosidase is generally less than about 1% of normal. In individuals with the late-onset form, the acid alpha-glucosidase is generally lower than about 40% of normal. [0069] “Metabolic acidosis” encompasses a reduced serum pH, and an abnormal serum bicarbonate concentration of <22 mEq/L, below the normal range of 22 to 29 mEq/L.

[0070] “Methylmalonic aciduria” relates to an inherited disorder in which the body is unable to properly digest specific fats and proteins, and the amino acids methionine, threonine, isoleucine and valine; which in turn leads to a buildup of a toxic level of methylmalonic acid in the blood.

[0071] “Disuse atrophy” relates to a temporary condition if the unused muscles are exercised properly after a limb is taken out of a cast or a person has regained enough strength to exercise after being bedridden for a period of time.

[0072] “Protein-energy wasting” relates to a loss of body protein mass and fuel reserves in a subject due to a maladaptive metabolic state. The maladaptive metabolic state includes nonspecific inflammatory processes, transient, intercurrent catabolic illnesses; nutrient losses into dialysate, acidemia, endocrine disorders such as resistance to insulin, growth hormone, and insulin-like growth factor-1, hyperglucagonemia, hyperparathyroidism, and loss of blood into the hemodialyzer, into feces or by blood drawing.

[0073] “Metabolic product” or “metabolite” relates to an intermediate or end product of metabolism. The term “metabolic product” or “metabolite” may relate to an intermediate or end product of metabolism related to muscular metabolism and/ or growth. In particular, the term “metabolic product” or “metabolite” may relate to an intermediate or end product of muscular metabolism.

EMBODIMENTS

[0074] In a first aspect, the present disclosure provides a method of treating and/or preventing a disease or condition associated with muscle decline and/or a kidney dysfunction. The method comprises administering to a subject in need thereof an effective amount of a composition comprising urolithin or an urolithin or a pharmaceutically acceptable salt thereof. In other words, the present disclosure provides a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof for use in a method of treating and/or preventing a disease or condition associated with muscle decline and/ or a kidney dysfunction. [00751 In one embodiment, the method is a method of treating at least one disease or condition associated with muscle decline and/or a kidney dysfunction. The method comprising administering to a subject having at least one disease or condition associated with muscle decline and/ or a kidney dysfunction a composition comprising a prophylactically effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof.

[0076] In another embodiment, the method is a method of preventing at least one disease or condition associated with muscle decline and/or a kidney dysfunction. The method comprises administering to a subject at risk of the at least one disease or condition associated with muscle decline and/ or a kidney dysfunction a composition comprising a prophylactically effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof.

[0077] In yet another embodiment, the muscle is tibialis anterior and/or extensor digitorum longus (EDL), and/or soleus muscle.

[0078] In one embodiment, the amount of the composition comprising trigonelline or the trigonelline or a pharmaceutically acceptable salt thereof is effective to decelerate glomerular filtration rate (GFR) progression and/ or decrease glomerular hyalinosis damage and/ or to improve the lean mass of a muscle.

[0079] In another embodiment, the amount of the composition comprising trigonelline or the trigonelline or a pharmaceutically acceptable salt thereof is effective to improve the lean mass of a muscle and/or to improve the muscle fiber size.

[0080] In a further embodiment the amount of the composition comprising trigonelline or the trigonelline or a pharmaceutically acceptable salt thereof is effective to improve the level of at least one nicotinamide adenine dinucleotide.

[0081] The present disclosure provides a method for improving and/or maintaining the mass of a muscle in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof. In other words, the present disclosure provides a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof for use in a method for improving and/or maintaining the mass of a muscle in a subject in need thereof. In particular, the amount of the composition comprising trigonelline or the trigonelline or a pharmaceutically acceptable salt thereof is effective to improve the lean mass of a muscle and/or to improve the muscle fiber size and/or to improve the level of at least one amino acid.

[0082] Thus, in another aspect, the present disclosure provides a method for improving the lean mass of a muscle in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof. In other words, the present disclosure provides a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof for use in a method for improving the lean mass of a muscle in a subject in need thereof.

[0083] In a related embodiment, the muscle is tibialis anterior and/or extensor digitorum longus (EDL), and/or soleus muscle.

[0084] In another aspect, the present disclosure provides a method for improving the muscle fiber size in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof. In other words, the present disclosure provides a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof for use in a method for improving the muscle fiber size in a subject in need thereof.

[0085] A decrease in muscle mass and fiber size may result in muscle atrophy. Thus, in one embodiment administering to the subject in need thereof an effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof reduces muscle atrophy.

[0086] In another aspect, the present disclosure provides a method for improving the level of at least one nicotinamide adenine dinucleotide in a muscle of a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof. In other words, the present disclosure provides a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof for use in a method for improving the level of at least one nicotinamide adenine dinucleotide in a muscle of a subject in need thereof. [0087] In one embodiment, the nicotinamide adenine dinucleotide is nicotinamide adenine dinucleotide in its oxidized form (NAD+) or reduced form (NADH). Preferably, the adenine dinucleotide is nicotinamide adenine dinucleotide in its oxidized form (NAD+).

[0088] In another embodiment, the nicotinamide adenine dinucleotide is nicotinamide adenine dinucleotide phosphate (NADP). In particular, the nicotinamide adenine dinucleotide is nicotinamide adenine dinucleotide phosphate in its oxidized form (NADP+) or reduced form (NADPH). Preferably, the adenine dinucleotide is nicotinamide adenine dinucleotide phosphate in its oxidized form (NAD+).

[0089] In one embodiment, administering to the subject in need thereof an effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof improves the antioxidant buffering capacity of the muscle.

[0090] In one embodiment, the methods disclosed herein can also be effective in the treatment of a disease or condition selected from chronic kidney disease, metabolic induced muscle wasting, end-stage renal disease, dialysis, diabetes, muscle loss and/or kidney failure due to hospitalization in the intensive care unit, Pompe disease, metabolic acidosis, methylmalonic aciduria, disuse atrophy, protein-energy wasting and combinations thereof.

[0091] In another embodiment the disease or condition is selected from the group consisting of chronic kidney disease, metabolic induced muscle wasting, end-stage renal disease, dialysis, diabetes, muscle loss and/or kidney failure due to hospitalization in the intensive care unit, Pompe disease, metabolic acidosis, methylmalonic aciduria, disuse atrophy, protein-energy wasting. Preferably the disease is chronic kidney disease.

[0092] In a further embodiment, the methods disclosed herein can also be effective in the treatment of an early stage of chronic kidney disease and/or a late stage of chronic kidney disease. Preferably, the early stage of chronic kidney disease are stages 2 and 3. In a certain embodiment the early stage of chronic kidney disease is stage 2. Preferably, the late stage of chronic kidney disease are stages 4 and 5. In a certain embodiment the late stage of chronic kidney disease is stage 4.

[0093] In one embodiment, the methods disclosed herein can also be effective in the treatment of an early stage of chronic kidney disease. [0094] In another embodiment, the methods disclosed herein can also be effective in the treatment of a late stage of chronic kidney disease.

[0095] In one embodiment, the amount of the composition comprising trigonelline or the trigonelline or a pharmaceutically acceptable salt thereof is effective to decelerate glomerular filtration rate (GFR) progression and/ or decrease glomerular hyalinosis damage and/ or to improve the lean mass of a muscle.

[0096] In a certain embodiment, the amount of the composition trigonelline or the trigonelline or a pharmaceutically acceptable salt thereof is effective to improve the lean mass of a muscle and/ or to improve the muscle fiber size and/ or to improve the level of at least one nicotinamide adenine dinucleotide.

[0097] In one embodiment, the composition comprising trigonelline or the trigonelline or a pharmaceutically acceptable salt thereof of the methods disclosed herein is administered in a composition selected from the group consisting of a food product, a food for special medical purposes (FSMP), a nutritional supplement, a dairy-based drink, a low-volume liquid supplement, a meal replacement beverage and combinations thereof. In particular, the composition may comprise additional supplements, such as minerals, vitamins and further bioactive substances such as N- acetylglucosamine or jV-acetyl mu ramie acid.

[0098] Accordingly, in another aspect, the present disclosure provides a nutritional composition for use in treating and/ or preventing a disease or condition associated with muscle decline and/or a kidney dysfunction. The nutritional composition comprises a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof.

[0099] In one embodiment the nutritional composition contains an amount of trigonelline effective for treating and/ or preventing a disease or condition associated with muscle decline and/or a kidney dysfunction in a subject in need thereof. In a related embodiment, the nutritional composition is formulated for oral administration.

[0100] In another aspect, the present disclosure provides a unit dosage form for use in treating and/or preventing a disease or condition associated with muscle decline and/or a kidney dysfunction. The unit dosage form comprises a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof. [oioi] In one embodiment the unit dosage form contains an amount of trigonelline effective for treating and/or preventing a disease or condition associated with muscle decline and/or a kidney dysfunction in a subject in need thereof. In a related embodiment, the unit dosage form is formulated for enteral administration.

[0102] In one embodiment, the amount of the nutritional composition and/or the unit dosage form is effective to decelerate glomerular filtration rate (GFR) progression and/or decrease glomerular hyalinosis damage and/or to improve the lean mass of a muscle.

[0103] In another embodiment, the amount of the nutritional composition and/or the unit dosage form is effective to improve the lean mass of a muscle and/or to improve the muscle fiber size and/or to improve the level of at least one nicotinamide adenine dinucleotide.

[0104] In an embodiment, the nutritional composition and/or the unit dosage form is selected from the group consisting of a food product, a food for special medical purposes (FSMP), a nutritional supplement, a dairy-based drink, a low-volume liquid supplement, a meal replacement beverage and combinations thereof.

[0105] Food products according to the present invention include, but are not limited to, breads, cakes, cookies, crackers, extruded snacks, potato products, rice products, corn products, wheat products, dairy products, yogurt, confectionery, hard candy, gummy candies, nutrition bar, breakfast cereal or beverage. A Food product according to the present invention may also be a plant-based drink such as a juice, a smoothie, soy milk, rice milk, or almond milk.

[0106] In a further embodiment, the nutritional composition and the unit dosage form disclosed herein can be administered to a subject in an early stage of chronic kidney disease and/or a late stage of chronic kidney disease.

[0107] In another embodiment, the nutritional composition and the unit dosage form disclosed herein can be administered to a subject in an early stage of chronic kidney disease.

[0108] In one embodiment, the nutritional composition and the unit dosage form disclosed herein can be administered to a subject in a late stage of chronic kidney disease. [0109] In another embodiment, trigonelline is administered in form a composition comprising trigonelline.

[0110] In a further embodiment, trigonelline in pure form or a pharmaceutically acceptable salt thereof is administered.

[0111] In one embodiment, the compositions disclosed herein further comprise at least one additive.

[0112] In another embodiment, trigonelline is micronized for more rapid dispersion or dissolution. If micronized trigonelline is used, then preferably the D₅₀ is under too pm, i.e., 50% by mass of the trigonelline or precursor thereof has a particle diameter size under too pm. More preferably, trigonelline or precursor thereof has a D₅₀ of under 75 pm, for example under 50 pm, for example under 25 pm, for example under 20 pm, for example under 10 pm. More preferably, trigonelline or precursor thereof has a D₅₀ in the range 0.5 to 50 pm, for example 0.5 to 20 pm, for example 0.5 to 10 pm, for example 1.0 to 10 pm, for example 1.5 to 7.5 pm, for example 2.8 to 5.5 pm. Preferably, trigonelline or precursor thereof has a D₉₀ size under too pm. More preferably, trigonelline or precursor thereof has a D₉₀ size under 75 pm, for example under 50 pm, for example under 25 pm, for example under 20 pm, for example under 15 pm. trigonelline or precursor thereof preferably has a D₉₀ in the range 5 to too pm, for example 5 to 50 pm, for example 5 to 20 pm, for example 7.5 to 15 pm, for example 8.2 to 16.0 pm.

[0113] Preferably, the trigonelline has a Dw in the range 0.5 - 1.0 pm. Preferably, the trigonelline has a D₉₀ in the range 8.2 to 16.0 pm, a D₅₀ in the range 2.8 to 5.5 pm and a Dw in the range 0.5 to 1.0 pm.

[0114] Miconization can be achieved by a method selected from the group consisting of compressive force milling, hammermilling, universal or pin milling, and jet milling such as spiral jet milling or fluidized-bed jet milling. Jet milling is particularly preferred.

[0115] Trigonelline is any compound comprising i-methylpyridin-i-ium-3-carboxylate including, for example, any salt thereof (e.g., Chloride or Iodide salt) and/or a form in which the ring therein may be reduced. [on6] Trigonelline could represented by the structure of formula 1, being able to establish a salt with an anion (X-), such as a halogen, for example, iodide or chloride. The structure of formula 1 is also known as 3-carboxy-i-methylpyridinium, N- Methylnicotinic acid, i-methylpyridine-3-carboxylic acid, i-methylpyridin-i-ium-3- carboxylic acid, Pyridinium 3-carboxy-i-methyl- hydroxide inner salt (8CI), 1- methylnicotinic acid, Pyridinium 3-carboxy-i-methyl-.

[on?] 1

[on8] In some embodiments, trigonelline is represented by the structure of formula 2 in its inner salt form. The structure of formula 2 is also known as Caffearine, Gynesine, N- Methylnicotinate, Trigenolline, Coffearine, Trigonellin, Coffearin, Betain nicotinate, Betaine nicotinate, i-methylpyridinium-3-carboxylate, Nicotinic acid N- methylbetaine, i-Methylpyridinio-3-carboxylate, i-Methyl-3-pyridiniumcarboxylate, N-Methylnicotinic acid, Trigenelline, Caffearin, 3-Carboxy-i-methylpyridinium hydroxide inner salt, N'-Methylnicotinate, i-methylpyridin-i-ium-3-carboxylate, 3- Carboxy-i-methylpyridinium hydroxide inner salt, Pyridinium 3-carboxy-i-methyl- hydroxide inner salt, i-methylpyridine-3-carboxylic acid, i-methylpyridin-i-ium-3- carboxylic acid, 1-methylnicotinate, Trigonelline (S), N-methyl-ni cotinate, Pyridinium 3-carboxy-i-methyl- hydroxide inner salt (8CI), N'-Methylnicotinic acid, N-Methylnicotinic acid betaine, Nicotinic acid N- methylbetaine, 1-Methyl-Nicotinic Acid Anion, Pyridinium 3-carboxy-i-methyl- inner salt, i-Methyl-5- (oxylatocarbonyl)pyridinium-3-ide, Pyridinium 3-carboxy-i-methyl- inner salt, 3- carboxy-i-methyl-Pyridinium hydroxide inner salt.

[01191 2

[0120] In some embodiments, optionally “trigonelline” can include metabolites and pyrolysis products thereof, such as nicotinamide, nicotinamide riboside, i- methylnicotinamide, i-methyl-2-pyridone-5-carboxamide (Me2PY), i-methyl-4- pyridone-5-carboxamide (Me4PY), and alkyl-pyridiniums, such as 1-methyl- pyridinium (NMP) and 1,4-dimethylpyridinium; although as noted later herein, some embodiments exclude one or more of these metabolites and pyrolysis products of trigonelline.

[0121] The composition can comprise a pharmacologically effective amount of trigonelline in a pharmaceutically suitable carrier. In aqueous liquid compositions, the trigonelline concentration preferably ranges from about 0.05 wt.% to about 4 wt.%, or from about 0.5 wt.% to about 2 wt.% or from about 1.0 wt.% to about 1.5 wt.% of the aqueous liquid composition.

[0122] In particular embodiments, the method is a treatment that augments the plasma trigonelline for example to a level in the range of 50 to 6000 nmol/L plasma, preferably too to 6000 nmol/L plasma. The method can comprise administering daily trigonelline in the weight range of 0.05 mg - 1 g per kg body weight, preferably 1 mg -200 mg per kg body weight, more preferably 5 mg - 150 mg per kg body weight, even more preferably 10 mg - 120 mg per kg body weight, or most preferably 40 mg - 80 mg per kg body weight.

[0123] For non-human mammals such as rodents, some embodiments comprise administering an amount of the composition that provides 1.0 mg to 1.0 g of the trigonelline / kg of body weight of the non-human mammal, preferably 10 mg to 500 mg of the trigonelline / kg of body weight of the non-human mammal, more preferably 25 mg to 400 mg of the trigonelline / kg of body weight of the mammal, most preferably 50 mg to 300 mg of the trigonelline / kg of body weight of the non-human mammal. [0124] For humans, some embodiments comprise administering an amount of the composition that provides 1.0 mg to 10.0 g of the trigonelline / kg of body weight of the human, preferably to mg to 5.0 g of the trigonelline / kg of body weight of the human, more preferably 50 mg to 2.0 g of the trigonelline / kg of body weight of the human, most preferably too mg to 1.0 g of the trigonelline / kg of body weight of the human.

[0125] In some embodiments, at least a portion of the trigonelline is isolated. Additionally or alternatively, at least a portion of trigonelline can be chemically synthesized.

[0126] In one embodiment, the composition comprises trigonelline which is chemically synthesized which is at least about 90% trigonelline, preferably at least about 98% trigonelline.

[0127] In a preferred embodiment, at least a portion of the trigonelline is provided by a plant or algae extract, for example an extract from one or more of coffee bean (e.g., a green coffee extract), Japanese radish, fenugreek seed, garden pea, hemp seed, oats, potato, dahlia, Stachys species, Strophanthus species, Laminariaceae species (especially Laminaria and Saccharina), Postelsia palmaeformis, Pseudochorda nagaii, Akkesiphycus or Dichapetalum cymosum. The plant extract is preferably enriched in trigonelline, i.e., the starting plant material comprises one or more other compounds in addition to the trigonelline, and the enriched plant material has a ratio of the trigonelline relative to at least one of the one or more other compounds that is higher than the ratio in the starting plant material.

[0128] Therefore, some embodiments of the composition comprise plant sources and/or enriched plant sources that provide at least a portion of the trigonelline in the composition.

[0129] In a preferred embodiment, the composition comprises enriched fenugreek extract which provides at least about 25 - 50% trigonelline in the composition. In a more preferred embodiment, the composition comprises enriched fenugreek extract which provides at least about 28 - 40% trigonelline.

[0130] In each of the compositions and methods disclosed herein, the composition is preferably a food product, including food additives, food ingredients, functional foods, dietary supplements, medical foods, nutraceuticals, oral nutritional supplements (ONS) or food supplements. [0131] The composition can be administered at least one day per week, preferably at least two days per week, more preferably at least three or four days per week (e.g., every other day), most preferably at least five days per week, six days per week, or seven days per week. The time period of administration can be at least one week, preferably at least one month, more preferably at least two months, most preferably at least three months, for example at least four months. In some embodiments, dosing is at least daily; for example, a subject may receive one or more doses daily, in an embodiment a plurality of doses per day. In some embodiments, the administration continues for the remaining life of the individual. In other embodiments, the administration occurs until no detectable symptoms of the medical condition remain. In specific embodiments, the administration occurs until a detectable improvement of at least one symptom occurs and, in further cases, continues to remain ameliorated.

[0132] In some embodiments, the trigonelline is 0.1 to 80 wt.% of the composition, for example 0.1 to 60 wt.% of the composition, such as 0.25 to 50 wt.% of the composition, 0.5-50 wt.% of the composition. If the composition is provided as part of or the whole of a meal, then the urolithin can be 0.25-5 wt.% of the composition, for example 0.3- 3 wt.% of the composition. If the composition is provided as a single serving supplement to a subject's general diet, then the urolithin can be 20 to 80 wt.% w/w of the composition, for example 20 to 40 wt.% of the composition, for example 25 to 35 wt.% of the composition.

[0133] The trigonelline can be administered in an amount of about 12 mg/day to about 9 g/day, preferably about 12 mg/day to about 7 g/day, more preferably about 12 mg/day to about 5 g/ day, most preferably about 12 mg/ day to about 3 g/ day, for example about 12 mg/day to about 900 mg/day, about 12 mg/day to about 700 mg/day, about 12 mg/day to about 500 mg/day, about 12 mg/day to about 250 mg/day, about 12 mg/day to about too mg/day, or about 12 mg/day to about 50 mg/day, or about 12 mg/day to about 20 mg/day, or about 12 mg/day to about 18 mg/day. Of course, the daily dose can be administered in portions at various hours of the day. However, in any given case, the amount of compound and/or composition administered will depend on such factors as the solubility of the active component, the formulation used, subject condition (such as weight), and/or the route of administration. For example, the daily doses of trigonelline disclosed above are non-limiting and, in some embodiments, may be different; in particular, the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof as disclosed herein can be utilized as an acute care food for special medical purposes (FSMP) and contain up to about too mg trigonelline / day. [0134] In one embodiment, Administration of the composition comprising trigonelline or the trigonelline or a pharmaceutically acceptable salt thereof may be carried out for at least about 2 or 3 months, preferably at least about 4 or 5 months, more preferably at least about 6 or 7 months in the remission phase, such as about 2 to 60 months, 2 to 48 months, 2 to 36 months, 2 to 24 months, or 2 to 12 months, preferably such as about 4 to 60 months, 4 to 48 months, 4 to 36 months, 4 to 24 months, or 4 to 12 months, etc.

[0135] In another embodiment, a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof is administered for about 1-2 weeks to 6 months, more preferably about 2 weeks to 4 months, more preferably about 3 weeks to 3 weeks, and most preferably about 4 weeks to 10 weeks to decelerate glomerular filtration rate (GFR) progression and/or decrease glomerular hyalinosis damage and/or to improve the lean mass of a muscle.

[0136] In a further embodiment, a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof is administered for 5 weeks to decelerate glomerular filtration rate (GFR) progression and/ or decrease glomerular hyalinosis damage and/ or to improve the lean mass of a muscle.

[0137] In another embodiment, the amount of the composition comprising trigonelline or the trigonelline or a pharmaceutically acceptable salt thereof is administered for 10 weeks to improve the lean mass of a muscle and/or to improve the muscle fiber size and/or to improve the level of at least one nicotinamide adenine dinucleotide.

[0138] The composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof as disclosed herein can use any of a variety of formulations for therapeutic administration. More particularly, pharmaceutical compositions can comprise appropriate pharmaceutically acceptable carriers or diluents and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. As such, administration of the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, and intratracheal administration. The active agent trigonelline may be systemic after administration or may be localized by the use of regional administration, intramural administration, or use of an implant that acts to retain the active dose at the site of implantation. [0139] In one embodiment, the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is administered enterally.

[0140] For oral preparations, the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose functional derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.

[0141] The composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof can be utilized in an aerosol formulation to be administered by inhalation. For example, the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof can be formulated into pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen and the like.

[0142] Furthermore, the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. The composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof can be administered rectally by a suppository. The suppository can include a vehicle such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.

[0143] Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof.

In another embodiment, the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is administered parenterally. Non-limiting examples of parenteral administration include intravenously, intramuscularly, intraperitoneally, subcutaneously, intraarticularly, intrasynovially, intraocularly, intrathecally, topically, and inhalation. As such, non-limiting examples of the form of the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof include natural foods, processed foods, natural juices, concentrates and extracts, injectable solutions, microcapsules, nano-capsules, liposomes, plasters, inhalation forms, nose sprays, nosedrops, eyedrops, sublingual tablets, and sustained-release preparations.

[0144] Unit dosage forms for injection or intravenous administration may comprise the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier, wherein each dosage unit, for example, mL or L, contains a predetermined amount of the composition containing one or more of the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof.

[0145] Compositions intended for a non-human animal include food compositions to supply the necessary dietary requirements for an animal, animal treats (e.g., biscuits), and/or dietary supplements. The compositions maybe a dry composition (e.g., kibble), semimoist composition, wet composition, or any mixture thereof. In one embodiment, the composition is a dietary supplement such as a gravy, drinking water, beverage, yogurt, powder, granule, paste, suspension, chew, morsel, treat, snack, pellet, pill, capsule, tablet, or any other suitable delivery form. The dietary supplement can comprise a high concentration of the UFA and NORC, and B vitamins and antioxidants. This permits the supplement to be administered to the animal in small amounts, or in the alternative, can be diluted before administration to an animal. The dietary supplement may require admixing, or can be admixed with water or other diluent prior to administration to the animal.

[0146] “Pet food” or “pet treat compositions” comprise from about 15% to about 50% crude protein. The crude protein material may comprise vegetable proteins such as soybean meal, soy protein concentrate, corn gluten meal, wheat gluten, cottonseed, and peanut meal, or animal proteins such as casein, albumin, and meat protein. Examples of meat protein useful herein include pork, lamb, equine, poultry, fish, and mixtures thereof. The compositions may further comprise from about 5% to about 40% fat. The compositions may further comprise a source of carbohydrate. The compositions may comprise from about 15% to about 60% carbohydrate. Examples of such carbohydrates include grains or cereals such as rice, corn, milo, sorghum, alfalfa, barley, soybeans, canola, oats, wheat, and mixtures thereof. The compositions may also optionally comprise other materials such as dried whey and other dairy byproducts.

[0147] In some embodiments, the ash content of the pet food composition ranges from less than 1% to about 15%, and in one aspect, from about 5% to about 10%.

[0148] The moisture content can vary depending on the nature of the pet food composition. In a one embodiment, the composition can be a complete and nutritionally balanced pet food. In this embodiment, the pet food may be a “wet food”, “dry food”, or food of intermediate moisture content. “Wet food” describes pet food that is typically sold in cans or foil bags, and has a moisture content typically in the range of about 70% to about 90%. “Dry food” describes pet food which is of a similar composition to wet food, but contains a limited moisture content, typically in the range of about 5% to about 15% or 20%, and therefore is presented, for example, as small biscuit-like kibbles. In one embodiment, the compositions have moisture content from about 5% to about 20%. Dry food products include a variety of foods of various moisture contents, such that they are relatively shelf-stable and resistant to microbial or fungal deterioration or contamination. Also included are dry food compositions which are extruded food products, such as pet foods, or snack foods for companion animals.

[0149] In another aspect, the present disclosure provides a method of increasing muscle stem cells and/or mitigating a decline of muscle stem cells, in a subject having diabetes, the method comprising administering to the subject having diabetes an effective amount of trigonelline or a pharmaceutically acceptable salt thereof. The muscle may be tibialis anterior and/or extensor digitorum longus (EDL), and/or soleus muscle. Preferably the trigonelline or pharmaceutically acceptable salt thereof is administered enterally or parenterally. The trigonelline or pharmaceutically acceptable salt thereof may be administered in a composition selected from the group consisting of a food product, a food for special medical purposes (FSMP), a nutritional supplement, a dairy-based drink, a low-volume liquid supplement, a meal replacement beverage, and combinations thereof. Preferably the trigonelline or pharmaceutically acceptable salt thereof is micronized. [0150] Examples

EXAMPLE 1

[0151] The following non-limiting example discusses experimental data that are investigated to further support the methods and compositions disclosed herein.

[0152] The renoprotective effects of trigonelline were assessed in a mouse model of type 2 diabetes (the db/db mouse).

[0153] A mouse model of diabetes was used endorsed by the Diabetic Complications Consortium (DiabComp/AMDCC), the db/db mouse model, which is obese and insulin resistant “type 2”. This mouse model has been shown to have a declined of NAD+ level in the kidney.

[0154] Mice were purchased from from Charles River (JAX Laboratory, United states), in order to obtain sizeable cohorts to run groups in tandem, which is crucial for reliable testing of kidney function. Seven week-old male db/db mice (n=8-io per group) received trigonelline by food administration (300 mg/kg/day) for a duration of 8 weeks. Db/m (control), db/db (diabetic) and db/db (diabetic + dapagliflozin (“dapa”) at iomg/kg/ day by gavage) mice were randomized to the following treatments:

[0155] Animals used were 8 db/m and 20 db/db procured from Charles River (JAX Laboratory, United states). The mice had free access to tap water and to standard rodent chow diet. All mice were kept in a room with constant temperature of ~25°C with 12 h day/ night cycle.

[0156] At baseline, mid-point and one week prior to euthanasia, before the Glomerular Filtration Rate (GFR) measurements, fresh urine samples were collected from each animal. Briefly, animals were singly housed into cages without litter until completion of the fresh urine samples collection. The volume of collected urine was placed into 2mL tubes and then immediately stored at -8o°C.

[0157] All analyses were performed by ANOVA followed by post hoc paired analysis using Tukey’s least significant difference method, correcting for multiple comparisons. A value for p<o.O5 was considered as statistically significant. A Z-score of 2 was used to exclude outliers.

[0158] Whole body composition including lean mass and fat mass were measured using EchoMRI at baseline, midpoint and endpoint. Overall, db/db mice (Diabetic) had an increase in fat mass and total body mass, and a decrease in lean mass when compared to db/m (Control), irrespective of treatment. Lean mass was slightly increased in db/db+trigonelline group when compared to the db/db+V group (Diabetic). The results are shown in FIG 1. In particular, the tibialis anterior, the quadriceps and the soleus of the db/db+trigonelline (+TG) group show a significantly increased muscle mass compared to the db/db+V group (Diabetic). The results are shown in FIG 2a, 2b and 2C.

[0159] The fiber size distribution and the number of fibers were measured on tibilais interior in mice after 8 weeks treatment with trigonelline, dosed at 300 mg/kg/day (+TG, db/db+trigo group) compared to a vehicle group (Diabetic, db/db+V group) and a control group (Control, db/m+V group) after 8 weeks treatment chow diet

[0160] The fiber size distribution and the number of fibers were determined after tibialis anterior cryosection, stained for the laminin protein and the myo-nucleus. All slides were acquired with the Olympus VS120 slide scanner microscope. The size of myofibers was calculated with Min Feret using an automated image processing algorithm developed internally using QuPath software and Fiji’s tool open-CSAM. The results are shown in FIG 3 and 4.

[0161] GFR progression was measure at baseline, midpoint and endpoint with a transdermal monitor device. FITC-sinistrin (50 mg/kg) was administered via the tail vein, the GFR was recorded for 1 hour and a half. At the end of the recording period, the transdermal GFR monitor device was removed and read out. Data were then analyzed using a dedicated software according to manufacturer recommendations. GFR progression was measured between midpoint and endpoint after 8 weeks treatment with trigonelline, dosed at 3oomg/kg/ day (+TG, db/db+trigo group) compared to a vehicle group (Diabetic, db/db+V group), control group (Control, db/m+V group) and dapa group (db/db+dapa group) after 8 weeks treatment chow diet, Fig. 5.

[0162] Hyalinosis was measured with a scoring system of no damage, intermediate damage, or severe damage, where hyalinosis refers to the thickening of the walls of the glomerular arterioles by the deposits of homogenous hyaline material after 8 weeks treatment with trigonelline, dosed at 300 mg/kg/day (+TG, db/db+trigonelline group) compared to a vehicle group (Diabetic, db/db+V group), control group (Control, db/m+V group) and dapa group (db/db+dapa group) after 8 weeks treatment chow diet, Fig. 6.

[0163] NAD+ level in kidney was measured in mice after 8 weeks treatment with trigonelline, dosed at 3oomg/kg/day (+trigonelline, db/db+trigonelline group) compared to a vehicle group (Diabetic, db/db+V group), control group (Healthy, db/m+V group) and dapa group (Diabetic, db/db+dapa group). The kidney NAD+ level was measured using a NAD/NADH kit, Fig. 7.

[0164] EXAMPLE 2

[0165] The following non-limiting example discusses experimental data that are investigated to further support the methods and compositions disclosed herein.

[0166] Frozen tibialis anterior muscles were sectioned at 10pm with a cryostat (Leica Biosystems). For Paxy staining, slides were fixed with 4% PFA and permeabilized in cold methanol. We next incubated the slides with primary antibodies anti-Paxy and with Hoechst 33342 for nuclei detection. Slides were then mounted using fluorescent mounting medium and imaged with an Olympus VS120 slide scanner. Images were analyzed using the VS-ASW FL software measurement tool. The number of Paxy positive cells was determined by manually counting on entire muscle sections.

[0167] As shown in FIG. 8, trigonelline increases the number of muscle stem cells in tibialis anterior muscle from mice after 8 weeks of treatment at 3oomg/kg/day. (+trigonelline, diabetic + Tg group) compared to a vehicle group (Diabetic group), control group (Healthy, non-diabetic group). Specifically, the quantification of muscle stem cells by Paxy marker in diabetic muscle has a decline compared to healthy, and trigonelline significantly rescues the number.

Claims

1. A method of treating and/ or preventing a disease or condition associated with muscle decline and/or a kidney dysfunction, the method comprising administering to a subject in need thereof an effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof.

2. The method of Claim 1, wherein the disease or condition is selected from chronic kidney disease, metabolic induced muscle wasting, end-stage renal disease, dialysis, diabetes, muscle loss and/or kidney failure due to hospitalization in the intensive care unit, Pompe disease, metabolic acidosis, methylmalonic aciduria, disuse atrophy, protein-energy wasting and combinations thereof.

3. The method of Claim 1, wherein the muscle decline and/or the kidney dysfunction is treated and/ or prevented in an early stage of chronic kidney disease and/ or a late stage of chronic kidney disease.

4. The method of Claim 1, wherein the muscle is tibialis anterior and/or extensor digitorum longus (EDL), and/or soleus muscle.

5. The method of Claim 1, wherein the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is administered enterally.

6. The method of Claim 1, wherein the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is administered parenterally.

7. The method of Claim 1, wherein the composition comprising trigonelline or the trigonelline or a pharmaceutically acceptable salt thereof is administered in a composition selected from the group consisting of a food product, a food for special medical purposes (FSMP), a nutritional supplement, a dairy-based drink, a low-volume liquid supplement, a meal replacement beverage, and combinations thereof.

8. The method of Claim 1, wherein the trigonelline is micronized.

9. A method of achieving at least one result selected from the group consisting of (i)decelerating glomerular filtration rate (GFR) progression; (ii) decreasing glomerular hyalinosis damage in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof.

10. The method of Claim 9, wherein the subject has a disease or condition selected from chronic kidney disease, metabolic induced muscle wasting, end-stage renal disease, dialysis, diabetes, muscle loss and/or kidney failure due to hospitalization in the intensive care unit, Pompe disease, metabolic acidosis, methylmalonic aciduria, disuse atrophy, protein-energy wasting and combinations thereof.

11. The method of Claim 9, wherein the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is administered enterally.

12. The method of Claim 9, wherein the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is administered parenterally.

13. The method of Claim 9, wherein the composition comprising trigonelline or the trigonelline or a pharmaceutically acceptable salt thereof is administered in a composition selected from the group consisting of a food product, a food for special medical purposes (FSMP), a nutritional supplement, a dairy-based drink, a low-volume liquid supplement, a meal replacement beverage and combinations thereof.

14. The method of Claim 9, wherein the trigonelline is micronized.

15. A method of achieving at least one result selected from the group consisting of (i) improving the lean mass of a muscle; (ii) improving the muscle fiber size; (iii) improving the level of at least one nicotinamide adenine dinucleotide in a muscle in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof.

16. The method of Claim 15, wherein the subject has a disease or condition selected from chronic kidney disease, metabolic induced muscle wasting, end-stage renal disease, dialysis, diabetes, muscle loss and/or kidney failure due to hospitalization in the intensive care unit, Pompe disease, metabolic acidosis, methylmalonic aciduria, disuse atrophy, protein-energy wasting and combinations thereof.

17. The method of Claim 15, wherein the lean mass of a muscle is improved in an early stage of chronic kidney disease and/or a late stage of chronic kidney disease.

18. The method of Claim 15, wherein the muscle is tibialis anterior and/or extensor digitorum longus (EDL), and/or soleus muscle.

19. The method of Claim 15, wherein muscle atrophy is reduced.

20. The method of Claim 15, wherein the at least one nicotinamide adenine dinucleotide is nicotinamide adenine dinucleotide in its oxidized form (NAD+) or reduced form (NADH).

21. The method of Claim 15, wherein the at least one nicotinamide adenine dinucleotide is nicotinamide adenine dinucleotide phosphate in its oxidized form (NADP+) or reduced form (NADPH).

22. The method of Claim 15, wherein the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is administered enterally.

23. The method of Claim 15, wherein the composition comprising trigonelline or the trigonelline or a pharmaceutically acceptable salt thereof is administered parenterally.

24. The method of Claim 15, wherein the composition comprising trigonelline or the trigonelline or a pharmaceutically acceptable salt thereof is administered in a composition selected from the group consisting of a food product, a food for special medical purposes (FSMP), a nutritional supplement, a dairy-based drink, a low-volume liquid supplement, a meal replacement beverage and combinations thereof.

25. The method of Claim 15, wherein the trigonelline is micronized.

26. A nutritional composition for use in treating and/or preventing a disease or condition associated with muscle decline and/ or a kidney dysfunction, comprising a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof; preferably the nutritional composition contains an amount of trigonelline effective for treating and/or preventing a disease or condition associated with muscle decline and/or a kidney dysfunction in a subject in need thereof.

27. The composition of Claim 26, containing an amount of trigonelline effective to decelerate glomerular filtration rate (GFR) progression and/or decrease glomerular hyalinosis damage and/ or to improve the lean mass of a muscle.

28. The composition of Claim 26, containing an amount of trigonelline effective to improve the lean mass of a muscle and/or to improve the muscle fiber size.

29. The composition of Claim 26, containing an amount of trigonelline effective to improve the level of at least one nicotinamide adenine dinucleotide.

30. The composition of Claim 26, wherein the muscle is tibialis anterior and/or extensor digitorum longus (EDL), and/or soleus muscle.

31. The composition of Claim 26, which is selected from the group consisting of a food product, a food for special medical purposes (FSMP), a nutritional supplement, a dairybased drink, a low-volume liquid supplement, a meal replacement beverage and combinations thereof.

32. The composition of Claim 26, wherein the composition is formulated for oral administration.

33. The composition of Claim 26, wherein the trigonelline is micronized.

34. A unit dosage form for use in treating and/ or preventing a disease or condition associated with muscle decline and/or a kidney dysfunction, comprising a composition comprising trigonelline or a trigonelline or a pharmaceutically acceptable salt thereof; preferably the unit dosage form contains an amount of trigonelline effective for treating and/or preventing a disease or condition associated with muscle decline and/or a kidney dysfunction in a subject in need thereof.

35. The unit dosage form of Claim 34, containing an amount of trigonelline effective to decelerate glomerular filtration rate (GFR) progression and/or decrease glomerular hyalinosis damage and/or to improve the lean mass of a muscle.

36. The unit dosage form of Claim 34, containing an amount of trigonelline effective to improve the lean mass of a muscle and/or to improve the muscle fiber size.

37. The unit dosage form of Claim 34, containing an amount of trigonelline effective to improve the level of at least one nicotinamide adenine dinucleotide.

38. The unit dosage form of Claim 34, wherein the muscle is tibialis anterior and/ or extensor digitorum longus (EDL), and/or soleus muscle.

39. The unit dosage form of Claim 34, which is selected from the group consisting of a food product, a food for special medical purposes (FSMP), a nutritional supplement, a dairybased drink, a low-volume liquid supplement, a meal replacement beverage and combinations thereof.

40. The unit dosage form of Claim 34, wherein the unit dosage form is formulated for enteral administration.

41. The unit dosage form of Claim 34, wherein the trigonelline is micronized.

42. A method of increasing muscle stem cells and/or mitigating a decline of muscle stem cells, in a subject having diabetes, the method comprising administering to the subject having diabetes an effective amount of trigonelline or a pharmaceutically acceptable salt thereof.

43. The method of Claim 42, wherein the muscle is tibialis anterior and/or extensor digitorum longus (EDL), and/or soleus muscle.

44. The method of Claim 42, wherein the trigonelline or pharmaceutically acceptable salt thereof is administered enterally.

45. The method of Claim 42, wherein the trigonelline or pharmaceutically acceptable salt thereof is administered parenterally.

46. The method of Claim 42, wherein the trigonelline or pharmaceutically acceptable salt thereof is administered in a composition selected from the group consisting of a food product, a food for special medical purposes (FSMP), a nutritional supplement, a dairybased drink, a low-volume liquid supplement, a meal replacement beverage, and combinations thereof.

47. The method of Claim 42, wherein the trigonelline or pharmaceutically acceptable salt thereof is micronized.