Methods and compositions comprising trigonelline for treating muscle decline and renal dysfunction

Abstract

The present disclosure relates generally to methods and compositions comprising trigonelline for treating or preventing diseases or conditions associated with muscle decline and / or renal dysfunction. In addition, the invention relates to methods and compositions comprising trigonelline for slowing the progression of glomerular filtration rate (GFR) and / or reducing glomerular vitreous lesion injury and / or increasing lean body mass of the muscle. In addition, methods and compositions comprising trigonelline are disclosed for increasing lean body mass of the muscle and / or increasing muscle fiber size. Also disclosed are methods for increasing the level of at least one nicotinamide adenine dinucleotide and compositions comprising trigonelline. Methods and compositions comprising trigonelline for increasing muscle stem cells and / or reducing muscle stem cell decline are also disclosed.

Description

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 523,960, filed June 29, 2023, the entirety of which is incorporated herein by reference.

[0002] The present disclosure relates generally to methods and compositions comprising trigonelline for treating or preventing a disease or condition associated with muscle wasting and / or renal dysfunction. Further, methods and compositions comprising trigonelline for slowing progression of glomerular filtration rate (GFR) and / or reducing glomerular hyalinosis injury and / or increasing lean body mass of muscle are related. Further, methods and compositions comprising trigonelline for increasing lean body mass of muscle and / or increasing muscle fiber size are disclosed. Methods and compositions comprising trigonelline for increasing levels of at least one nicotinamide adenine dinucleotide are also disclosed. BACKGROUND

[0003] Muscle mass loss that occurs during muscle wasting can 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, results in a decrease in muscle mass and muscle wasting.

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

[0005] Muscle wasting is a common complication of CKD characterized by loss of muscle mass, strength, and function, which significantly increases the risk of morbidity and mortality in this population. Many complications associated with declining kidney 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 kidney’s ability to excrete waste, concentrate urine, reabsorb proteins and amino acids, and conserve electrolytes. Unlike the sudden but reversible kidney function that accompanies acute kidney failure, the kidney function of chronic kidney disease progresses and worsens irreversibly until end-stage renal disease (ESRD). CKD originates from multiple heterogeneous pathogenic pathways that irreversibly alter the function and structure of the kidney over months or years.

[0007] Diabetes and hypertension are the leading causes of CKD in all high- and middle-income countries and in many low-income countries. The incidence, prevalence, and progression of CKD also vary within countries by race and social determinants of health, possibly through epigenetic influences. Many people are asymptomatic or have non-specific symptoms such as lethargy, itching, or loss of appetite. The disease is often diagnosed incidentally after screening tests such as urine dipsticks or blood tests, or when symptoms become severe. The best available indicator of overall kidney function is glomerular filtration rate (GFR). Disease and management are classified according to stage of severity, with assessment based on GFR and proteinuria and clinical diagnosis (etiology and pathology). The presence of proteinuria is associated with an increased risk of progression of CKD. Diagnosis of CKD relies on the determination of chronic reduction in kidney function and structural kidney damage.

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

[0009] In a first aspect, the present disclosure provides a method of treating and / or preventing a disease or condition associated with muscle wasting and / or kidney dysfunction. The method includes administering to an individual in need thereof an effective amount of a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof. In one embodiment, the muscle wasting and / or kidney dysfunction is treated and / or prevented in the early stages of chronic kidney disease and / or in the late stages of chronic kidney disease.

[0010] In another aspect, the present disclosure provides a method for slowing the progression of glomerular filtration rate (GFR) in an individual in need thereof. The method includes administering to the individual in need thereof an effective amount of a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof.

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

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

[0013] In some embodiments of the above 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 increasing muscle fiber size in an individual in need thereof, the method comprising administering to the individual in need thereof an effective amount of a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof.

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

[0016] In some embodiments of the foregoing aspects, the individual has a disease or disorder selected from the group consisting of chronic kidney disease, metabolic-induced muscle wasting, end-stage renal disease, dialysis, diabetes, muscle loss due to hospitalization in an intensive care unit, and / or renal failure, Pompe disease, metabolic acidosis, methylmalonic aciduria, disuse atrophy, protein-energy wasting, and combinations thereof.

[0017] In other embodiments, the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is administered enterally.

[0018] In further embodiments, the composition comprising trigonelline or 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 the treatment and / or prevention of a disease or disorder associated with muscle decline and / or renal dysfunction. The nutritional composition comprises a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof. Preferably, the nutritional composition comprises an amount of trigonelline effective to treat and / or prevent a disease or disorder associated with muscle decline and / or renal dysfunction in an individual 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 milk-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 disorder associated with muscle decline and / or renal dysfunction. The unit dosage form comprises a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof. Preferably, the unit dosage form comprises an amount of trigonelline effective to treat and / or prevent a disease or disorder associated with muscle decline and / or renal dysfunction in an individual 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 purpose (FSMP), a nutritional supplement, a milk-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 unit dosage form contains Trigonelline in an amount effective to slow progression of glomerular filtration rate (GFR) and / or reduce glomerular hyalinosis damage and / or increase lean body mass of muscle.

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

[0028] In other embodiments, the muscle is tibialis anterior muscle 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 reducing muscle stem cell decline in an individual having diabetes, the method comprising administering to the individual having diabetes an effective amount of Trigonelline or a pharmaceutically acceptable salt thereof. The muscle can be tibialis anterior muscle and / or extensor digitorum longus (EDL) and / or soleus muscle. Preferably, the Trigonelline or a pharmaceutically acceptable salt thereof is administered enterally or parenterally. The Trigonelline or a pharmaceutically acceptable salt thereof can be administered in a composition selected from the group consisting of a food product, a food for special medical purpose (FSMP), a nutritional supplement, a milk-based drink, a low volume liquid supplement, a meal replacement beverage, and combinations thereof. Preferably, the Trigonelline or a 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 stabilize kidney dysfunction.

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

[0033] An advantage of one or more aspects and embodiments provided by the present disclosure is to help increase lean body mass of muscle.

[0034] Another advantage of one or more aspects and embodiments provided by the present disclosure is to help slow progression of glomerular filtration rate (GFR).

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

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

[0037] Another advantage of one or more aspects and embodiments provided by the present disclosure is to increase 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 muscle bioenergetic nucleotides and nucleotides important for cell signaling.

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

[0041] Figure 1 Lean body mass measured in mice treated with trigonelline for 8 weeks (end point) dosed at 300 mg / kg / day (+TG, db / db + trigonelline group) compared to vehicle group (Diabetic, db / db + V group), control group (Control, db / m + V group), and dapa group (dapa, db / db + dapa group). EchoMRI was used to measure lean body mass.

[0042] Figure 2a Muscle mass of tibialis anterior muscle measured in grams after 8 weeks of treatment with trigonelline dosed at 300 mg / kg / day (+TG, db / db + trigonelline group) compared to vehicle group (Diabetic, db / db + V group), control group (Control, db / m + V group), and dapa group (dapa, db / db + dapa group). Muscle mass of tibialis anterior muscle was measured by weighing on a precision balance.

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

[0044] Figure 2cMuscle mass of the gastrocnemius muscle measured in grams after 8 weeks of treatment with trigonelline, administered at 300 mg / kg / day (+TG, db / db + trigonelline group), compared to the vehicle group (Diabetic, db / db + V group), the control group (Control, db / m + V group) and the dapa group (dapa, db / db + dapa group). Muscle mass of the tibialis anterior muscle was measured by weighing on a precision balance.

[0045] Figure 3 Fiber size distribution measured by immunofluorescence after 8 weeks of treatment with trigonelline, administered at 300 mg / kg / day (+TG, db / db + trigonelline group), compared to the vehicle group (Diabetic, db / db + V group), the control group (Control, db / m + V group) and the dapa group (dapa, db / db + dapa group). Fiber size distribution was measured by an automated image processing algorithm.

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

[0047] Figure 5 Δ Glomerular filtration rate measured between 4 weeks (midpoint) and 8 weeks (endpoint) of treatment with trigonelline, administered at 300 mg / kg / day (+TG, db / db + trigonelline group), compared to the vehicle group (Diabetic, db / db + V group), the control group (Control, db / m + V group) and the dapa group (dapa, db / db + dapa group). Glomerular filtration rate was measured using a transdermal GFR monitoring device after intravenous injection of FITC-phlecomycin (50 mg / kg).

[0048] Figure 6 Glomerular hyalinosis lesions measured after 8 weeks (endpoint) of treatment with trigonelline, administered at 300 mg / kg / day (+TG, db / db + trigonelline group), compared to the vehicle group (Diabetic, db / db + V group), the control group (Control, db / m + V group) and the dapa group (dapa, db / db + dapa group). Glomerular hyalinosis lesions were determined using periodic acid Schiff staining.

[0049] Figure 7NAD+ levels measured after 8 weeks of treatment with trigonelline are shown for 300 mg / kg / day dosing (+trigonelline, db / db + trigonelline group) and compared to vehicle group (diabetic, db / db + V group) and control group (healthy, db / m + V group). NAD / NADH kit was used to measure kidney NAD+ levels.

[0050] Figure 8 is a graphical representation showing experimental results of Example 2 disclosed herein. DETAILED DESCRIPTION

[0051] DEFINITIONS

[0052] Some definitions are provided below. Nonetheless, definitions can be located in the "EMBODIMENTS" section below and the heading "DEFINITIONS" above does not mean that such disclosure in the "EMBODIMENTS" section is not a definition.

[0053] All percentages expressed herein are by weight of the total composition, unless expressed otherwise. As used herein, "about," "approximately," and "substantially" shall be understood to mean within a range of numbers, for example, within -10% to +10% of the value in question, preferably within -5% to +5% of the value in question, more preferably within -1% to +1% of the value in question, most preferably within -0.1% to +0.1% of the value in question. All numerical ranges herein should be interpreted as including the integers or fractions within the range. Additionally, these numerical ranges are to be construed in a manner similar to that of limits recited by a patent claim to be supported by the specification unless otherwise explicitly indicated. For example, a disclosure of a range such as 1 to 10 should be interpreted to include ranges of 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, etc.

[0054] As used in the disclosure and 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.

[0055] The words "comprise," "comprises," "comprising," "include," "includes," and "including" when used in this specification and in the following claims are intended to specify the presence of stated features, integers, components, or operations, but they do not preclude the presence or addition of one or more other features, integers, components, operations, or groups thereof. As used herein, the term "about" means that quantities, dimensions, sizes, formulations, parameters, shapes and other

[0056] The term "and / or," even if used in the alternative (e.g., "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 "both X and Y." For example, "muscle wasting and / or kidney dysfunction" should be interpreted as "muscle wasting," or "kidney dysfunction," or "both muscle wasting and kidney dysfunction."

[0057] As used herein, the terms "example" and "such as," when used in this specification and in the following claims, are intended to introduce example(s) or instances that do not exhaustively or exclusively list items. As used herein, a condition is "associated with" or "linked to" another condition if the two conditions occur simultaneously, preferably meaning that the two conditions are caused by the same underlying condition, and most preferably meaning that one of the identified conditions is caused by the other identified condition.

[0058] “Prevention” includes reducing the risk and / or severity of a condition or disorder. The terms “treatment” and “remission” include both prophylactic or preventative treatments (preventing and / or delaying development of a target pathologic condition or disorder) as well as curative, therapeutic or disease-modifying treatments, including therapeutic measures that cure, slow down, lessen symptoms of, and / or halt progression of a diagnosed pathologic condition or disorder; and treatments of patients at risk for becoming afflicted or suspected to be afflicted, as well as treatments of patients afflicted or diagnosed with a disease or medical condition. The term does not necessarily imply that a subject is treated until total recovery. The term “treatment” also refers to health maintenance and / or promotion in individuals who are not ill but who can be susceptible to an unhealthy condition. The terms “treatment” and “remission” are also intended to include fortification or otherwise enhancing one or more primary prophylactic or therapeutic measures. The terms “treatment” and “remission” are also intended to include dietary management of a disease or condition or for preventing or preventing a disease or condition. Treatment can be patient- or physician-related.

[0059] An “individual” or “subject” is a mammal, preferably a human. The term mammal can include, but is not limited to, a pet or livestock. In particular, the term “livestock” can include, but is not limited to, a horse (e.g., a pet or horse undergoing medical treatment), or a cow or poultry (e.g., a cow or poultry used in agriculture). In particular, the term “pet” can include, but is not limited to, a senior pet (e.g., a cat older than 10 years or a dog older than 7 years), a pet with obesity, a pet with diabetes, and a pet with CKD.

[0060] As used herein, an “effective amount” is an amount that prevents a deficiency, treats a disease or medical condition in an individual, or, in general, alleviates symptoms, manages progression of a disease, or provides a nutritional, physiological, or medical benefit to an individual. The relative terms “improve,” “increase,” “enhance,” and the like refer to the effect of a composition disclosed herein (i.e., a composition comprising urolithin or a pharmaceutically acceptable salt thereof).

[0061] The terms “food,” “food product,” and “food composition” mean a product or composition intended for ingestion by an individual (such as a human) and that provides at least one nutrient to the individual. A food product typically includes at least one of protein, lipid, carbohydrate, and optionally one or more vitamins and minerals. The compositions of the present disclosure, including the various embodiments described herein, can include, consist of, or consist essentially of the elements described herein, as well as any additional or optional ingredients, components, or elements described herein or otherwise useful in a diet.

[0062] The term "unit dosage form" as used herein refers to physically discrete units suitable as unitary dosages for human and animal individuals, 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 specification for unit dosage forms depends on the particular compound and / or composition employed and the effect to be achieved, and the pharmacodynamics associated with each compound and / or composition in the host.

[0063] "Chronic Kidney Disease (CKD)" encompasses the presence of kidney damage (i.e., proteinuria) or reduced kidney function (i.e., a GFR < 60 mL / min / 1.73 m 2 , GFR < 60 mL / min) for 3 months or more, regardless of the clinical diagnosis. CKD is classified into five stages based on GFR: > 90 mL / min / 1.73 m (Stage 1), 60-89 mL / min / 1.73 m (Stage 2), 30-59 mL / min / 1.73 m (Stage 3), 15-29 mL / min / 1.73 m (Stage 4), and < 15 mL / min / 1.73 m (Stage 5).

[0064] "Early stage of chronic kidney disease" encompasses chronic kidney disease in Stage 2 and Stage 3 based on GFR: 60-89 mL / min / 1.73 m (Stage 2), 30-59 mL / min / 1.73 m (Stage 3). Preferably, "early stage of chronic kidney disease" encompasses chronic kidney disease in Stage 2 based on GFR: 60-89 mL / min / 1.73 m.

[0065] "Late stage of chronic kidney disease" encompasses chronic kidney disease in Stage 4 and Stage 5 based on GFR: 15-29 mL / min / 1.73 m (Stage 4), and < 15 mL / min / 1.73 m (Stage 5). Preferably, "late stage of chronic kidney disease" encompasses chronic kidney disease in Stage 4 based on GFR: 15-29 mL / min / 1.73 m.

[0066] "End-Stage Renal Disease (ESRD)" encompasses the condition of individuals with CKD who require renal replacement therapy. Preferably, ESRD encompasses chronic kidney disease in Stage 5 based on GFR: < 15 mL / min / 1.73 m.

[0067] "Metabolism-induced muscle wasting" encompasses a prolonged catabolic state in which the rate of muscle protein breakdown exceeds that of protein synthesis.

[0068] “Diabetes” encompasses both Type I and Type II forms of the disease. Non-limiting examples of risk factors for diabetes include a waist circumference greater than 40 inches for men or 35 inches for women, a blood pressure of 130 / 85 mm Hg or higher, triglycerides higher than 150 mg / dl, fasting blood glucose higher than 100 mg / dl, or high-density lipoprotein lower than 40 mg / dl for men or 50 mg / dl for women.

[0069] “Pompe disease” encompasses classic infantile, non-classic infantile, and late-onset. In children with classic or non-classic infantile Pompe disease, the activity of acid alpha-glucosidase is typically less than about 1% of normal. In individuals with late-onset, acid alpha-glucosidase is typically less than about 40% of normal.

[0070] “Metabolic acidosis” encompasses a decreased serum pH and an abnormal serum bicarbonate concentration of <22 mEq / L, which is outside the normal range of 22 mEq / L to 29 mEq / L.

[0071] “Methylmalonic aciduria” relates to a genetic disorder in which the body cannot properly digest certain fats and proteins, as well as the amino acids methionine, threonine, isoleucine, and valine; this in turn leads to the accumulation of toxic levels of methylmalonic acid in the blood.

[0072] “Disuse atrophy” relates to a temporary condition that can be improved by proper exercise of muscles not used after limb removal in a cast, or that have regained sufficient strength to exercise after a period of bed rest.

[0073] “Protein-energy consumption” relates to the loss of body protein mass and fuel reserves in an individual due to maladaptive metabolic states. Maladaptive metabolic states include: non-specific inflammatory processes, transient combined catabolic illness; nutrient loss to dialysate, acidosis, endocrine disorders (such as insulin, growth hormone, and insulin-like growth factor-1 resistance), hyperglucagonemia, hyperparathyroidism, and blood loss to a hemodialyzer, feces, or from blood draws.

[0074] “Metabolic product” or “metabolite” relates to an intermediate or end product of metabolism. The term “metabolic product” or “metabolite” can relate to an intermediate or end product of metabolism associated with muscle metabolism and / or growth. In particular, the term “metabolic product” or “metabolite” can relate to an intermediate or end product of muscle metabolism.

[0075] Embodiments

[0076] 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 kidney dysfunction. The method includes administering to an individual in need thereof an effective amount of a composition comprising a urolithin or a urolithin or a pharmaceutically acceptable salt thereof. In other words, the present invention provides a method for treating and / or preventing a disease or condition associated with muscle decline and / or kidney dysfunction comprising a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof.

[0077] In one embodiment, the method is a method of treating at least one disease or condition associated with muscle decline and / or kidney dysfunction. The method includes administering to an individual having at least one disease or condition associated with muscle decline and / or kidney dysfunction a composition comprising a prophylactically effective amount of a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof.

[0078] In another embodiment, the method is a method of preventing at least one disease or condition associated with muscle decline and / or kidney dysfunction. The method includes administering to an individual at risk of having at least one disease or condition associated with muscle decline and / or kidney dysfunction a composition comprising a prophylactically effective amount of a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof.

[0079] In yet another embodiment, the muscle is tibialis anterior and / or extensor digitorum longus (EDL) and / or soleus muscle.

[0080] In one embodiment, the amount of the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is effective to slow progression of glomerular filtration rate (GFR) and / or reduce glomerular hyalinosis injury and / or increase lean body mass of muscle.

[0081] In another embodiment, the amount of the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is effective to increase lean body mass of muscle and / or increase muscle fiber size.

[0082] In another embodiment, the amount of the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is effective to increase levels of at least one nicotinamide adenine dinucleotide.

[0083] The present disclosure provides a method for increasing and / or maintaining muscle mass in an individual in need thereof, the method comprising administering to the individual in need thereof an effective amount of a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof. In other words, the present disclosure provides a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof for use in a method for increasing and / or maintaining muscle mass in an individual in need thereof. In particular, the amount of the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is effective to increase lean body mass of muscle and / or increase muscle fiber size and / or increase the level of at least one amino acid.

[0084] Thus, in another aspect, the present disclosure provides a method for increasing lean body mass of muscle in an individual in need thereof, the method comprising administering to the individual in need thereof an effective amount of a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof. In other words, the present disclosure provides a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof for use in a method for increasing lean body mass of muscle in an individual in need thereof.

[0085] In related embodiments, the muscle is tibialis anterior and / or extensor digitorum longus (EDL) and / or soleus.

[0086] In another aspect, the present disclosure provides a method for increasing muscle fiber size in an individual in need thereof, the method comprising administering to the individual in need thereof an effective amount of a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof. In other words, the present disclosure provides a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof for use in a method for increasing muscle fiber size in an individual in need thereof.

[0087] Reduction in muscle mass and fiber size can result in muscle atrophy. Thus, in one embodiment, administering to the individual in need thereof an effective amount of a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof can reduce muscle atrophy.

[0088] In another aspect, the present disclosure provides a method for increasing the level of at least one nicotinamide adenine dinucleotide in muscle in an individual in need thereof, the method comprising administering to the individual in need thereof an effective amount of a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof. In other words, the present disclosure provides a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof for use in a method for increasing the level of at least one nicotinamide adenine dinucleotide in muscle in an individual in need thereof.

[0089] 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+).

[0090] 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+).

[0091] In one embodiment, administering to an individual in need thereof an effective amount of a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is effective to increase the antioxidant buffering capacity of muscle.

[0092] In one embodiment, the methods disclosed herein are also effective to treat a disease or condition selected from the group consisting of chronic kidney disease, metabolic-induced muscle wasting, end-stage renal disease, dialysis, diabetes, muscle loss and / or renal failure due to hospitalization in an intensive care unit, Pompe disease, metabolic acidosis, methylmalonic aciduria, disuse atrophy, protein-energy wasting, and combinations thereof.

[0093] 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 renal failure due to hospitalization in an intensive care unit, Pompe disease, metabolic acidosis, methylmalonic aciduria, disuse atrophy, protein-energy wasting. Preferably, the disease is chronic kidney disease.

[0094] In further embodiments, the methods disclosed herein are also effective to treat early stage chronic kidney disease and / or late stage chronic kidney disease. Preferably, the early stage chronic kidney disease is stage 2 and stage 3. In a certain embodiment, the early stage chronic kidney disease is stage 2. Preferably, the late stage chronic kidney disease is stage 4 and stage 5. In a certain embodiment, the late stage chronic kidney disease is stage 4.

[0095] In one embodiment, the methods disclosed herein are also effective to treat early stage chronic kidney disease.

[0096] In another embodiment, the methods disclosed herein are also effective to treat late stage chronic kidney disease.

[0097] In one embodiment, the amount of the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is effective to slow progression of glomerular filtration rate (GFR) and / or reduce glomerular hyalinosis injury and / or increase lean body mass of muscle.

[0098] In another embodiment, the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is in an amount effective to increase lean body mass of muscle and / or increase muscle fiber size and / or increase levels of at least one nicotinamide adenine dinucleotide.

[0099] In one embodiment, the composition comprising trigonelline or 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 milk-based drink, a low volume liquid supplement, a meal replacement beverage, and combinations thereof. In particular, the composition can comprise additional supplements such as minerals, vitamins, and additional bioactive substances such as N-acetylglucosamine or N-acetylmuramic acid.

[0100] Thus, in another aspect, the present disclosure provides a nutritional composition for use in the treatment and / or prevention of a disease or condition associated with muscle decline and / or kidney dysfunction. The nutritional composition comprises a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof.

[0101] In one embodiment, the nutritional composition contains trigonelline in an amount effective to treat and / or prevent a disease or condition associated with muscle decline and / or kidney dysfunction in an individual in need thereof. In a related embodiment, the nutritional composition is formulated for oral administration.

[0102] In another aspect, the present disclosure provides a unit dosage form for use in the treatment and / or prevention of a disease or condition associated with muscle decline and / or kidney dysfunction. The unit dosage form comprises a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof.

[0103] In one embodiment, the unit dosage form contains trigonelline in an amount effective to treat and / or prevent a disease or condition associated with muscle decline and / or kidney dysfunction in an individual in need thereof. In a related embodiment, the unit dosage form is formulated for enteral administration.

[0104] In one embodiment, the nutritional composition and / or unit dosage form is in an amount effective to slow progression of glomerular filtration rate (GFR) and / or reduce glomerular hyaline lesions and / or increase lean body mass of muscle.

[0105] In another embodiment, the nutritional composition and / or unit dosage form is in an amount effective to increase lean body mass of muscle and / or increase muscle fiber size and / or increase levels of at least one nicotinamide adenine dinucleotide.

[0106] In embodiments, the nutritional composition and / or unit dosage form is selected from the group consisting of a food product, a food for special medical purpose (FSMP), a nutritional supplement, a milk-based drink, a low volume liquid supplement, a meal replacement beverage, and combinations thereof.

[0107] The food product according to the present application includes, but is not limited to, bread, cake, cookie, wafer, extruded snack, potato product, rice product, corn product, wheat product, dairy product, yogurt, candy, hard candy, soft candy, nutritional bar, breakfast cereal or beverage. The food product according to the present application can also be a plant-based drink such as a juice, a milkshake, a soy milk, a rice milk or an almond milk.

[0108] In further embodiments, the nutritional composition and unit dosage form disclosed herein can be administered to an individual in the early stage of chronic kidney disease and / or in the late stage of chronic kidney disease.

[0109] In another embodiment, the nutritional composition and unit dosage form disclosed herein can be administered to an individual in the early stage of chronic kidney disease.

[0110] In one embodiment, the nutritional composition and unit dosage form disclosed herein can be administered to an individual in the late stage of chronic kidney disease.

[0111] In another embodiment, trigonelline is administered in the form of a composition comprising trigonelline.

[0112] In further embodiments, trigonelline or a pharmaceutically acceptable salt thereof is administered in pure form.

[0113] In one embodiment, the composition disclosed herein further comprises at least one additive.

[0114] In another embodiment, trigonelline is micronized to disperse or dissolve more rapidly. If micronized trigonelline is used, it is preferred that the D 50 less than 100 pm, i.e. 50 mass% of the trigonelline or precursor thereof has a particle size dimension of less than 100 pm. More preferably, the D 50 less than 75 pm, such as less than 50 pm, such as less than 25 pm, such as less than 20 pm, such as less than 10 pm. More preferably, the D 50 in the range of 0.5 pm to 50 pm, such as 0.5 pm to 20 pm, such as 0.5 pm to 10 pm, such as 1.0 pm to 10 pm, such as 1.5 pm to 7.5 pm, such as 2.8 pm to 5.5 pm. Preferably, the D 90 less than 100 pm. More preferably, the D 90less than 75 pm, such as less than 50 pm, such as less than 25 pm, such as less than 20 pm, such as less than 15 pm. D of trigonelline or a precursor thereof 90 preferably 5 pm to 100 pm, such as 5 pm to 50 pm, such as 5 pm to 20 pm, such as 7.5 pm to 15 pm, such as 8.2 pm to 16.0 pm.

[0115] preferably D of trigonelline 10 in the range of 0.5 pm to 1.0 pm. Preferably D of trigonelline 90 in the range of 8.2 pm to 16.0 pm, D 50 in the range of 2.8 pm to 5.5 pm and D 10 in the range of 0.5 pm to 1.0 pm.

[0116] Micronization can be achieved by a method selected from the group consisting of compression force milling, hammer milling, general milling or pin milling, and jet milling (such as spiral jet milling or fluid bed jet milling). Particularly preferred is jet milling.

[0117] “Trigonelline” is any compound comprising a 1-methylpyridinium-1-olate salt, including for example any salt thereof (e.g. a chloride salt or an iodide salt) and / or a form wherein the ring can be reduced.

[0118] In some embodiments, trigonelline is represented by the structure of Formula 1, which is capable of forming a salt with an anion (X ) such as a halogen (e.g. iodide or chloride). The structure of Formula 1 is also known as 3-carboxy-1-methylpyridinium, N-methyl nicotinic acid, 1-methylpyridine-3-carboxylic acid, 1-methylpyridinium-1-olate, pyridinium-3-carboxy-1-methyl-hydroxide inner salt (8CI), 1-methyl nicotinic acid, pyridinium-3-carboxy-1-methyl.

[0119]

[0120] 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 Caffeine Base, Gynesine, N- Methyl Nicotinate, Trigenolline, Coffeine, Trigonellin, Coffearin, Nicotinic Betaine, Nicotinic Inner Salts, 1 -Methyl Pyridinium-3-carboxylate, Nicotinic N-Methyl Betaine, 1 -Methyl Pyridinium-3-carboxylate, 1 -Methyl-3-pyridinium carboxylate, N-Methyl Nicotinic Acid, Trigenelline, Caffearin, 3-Carboxy-1 -methyl pyridinium hydroxide inner salt, N'-Methyl Nicotinate, 1 -Methyl Pyridinium-1 -onium-3-carboxylate, 3-Carboxy-1 -methyl pyridinium hydroxide inner salt, Pyridinium 3-carboxy-1 -methyl-hydroxide inner salt, 1 -Methyl pyridine-3-carboxylic acid, 1 -Methyl pyridinium-1 -onium-3-carboxylic acid, 1 -Methyl nicotinate, Trigonelline (S), N-Methyl-nicotinate, Pyridinium 3-carboxy-1 -methyl-hydroxide inner salt (8CI), N'-Methyl nicotinic acid, N-Methyl nicotinic betaine, Nicotinic N-methyl betaine, 1 -Methyl-nicotinic anion, Pyridinium 3-carboxy-1 -methyl-inner salt, 1 -Methyl-5-(oxycarbonyl)pyridinium-3-anion, Pyridinium 3-carboxy-1 -methyl-inner salt, 3-Carboxy-1 -methyl-pyridinium hydroxide inner salt.

[0121]

[0122] In some embodiments, optionally, "trigonelline" can include metabolites and pyrolysis products thereof, such as nicotinamide, nicotinamide riboside, 1 -methyl nicotinamide, 1 -methyl-2-pyridone-5-carboxamide (Me2PY), 1 -methyl-4-pyridone-5-carboxamide (Me4PY), and alkyl pyridiniums such as 1 -methyl pyridinium (NMP) and 1,4-dimethyl pyridinium; although as noted later herein, some embodiments do not include one or more of these metabolites and pyrolysis products of trigonelline.

[0123] The composition can include a pharmacologically effective amount of trigonelline and a pharmaceutically suitable carrier. In an aqueous liquid composition, the concentration of trigonelline is preferably in the range of about 0.05% to about 4% by weight, or about 0.5% to about 2% by weight, or about 1.0% to about 1.5% by weight of the aqueous liquid composition.

[0124] In certain embodiments, the method is a treatment that increases plasma trigonelline levels to a level in the range of, for example, 50 nmol / L plasma to 6000 nmol / L plasma, preferably 100 nmol / L plasma to 6000 nmol / L plasma. The method can include administering a 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 of trigonelline per day.

[0125] For non-human mammals, such as rodents, some embodiments include administering an amount of the composition that provides 1.0 mg to 1.0 g of trigonelline per kg of non-human mammal body weight, preferably 10 mg to 500 mg of trigonelline per kg of non-human mammal body weight, more preferably 25 mg to 400 mg of trigonelline per kg of mammal body weight, most preferably 50 mg to 300 mg of trigonelline per kg of non-human mammal body weight.

[0126] For humans, some embodiments include administering an amount of the composition that provides 1.0 mg to 10.0 g of trigonelline per kg of human body weight, preferably 10 mg to 5.0 g of trigonelline per kg of human body weight, more preferably 50 mg to 2.0 g of trigonelline per kg of human body weight, most preferably 100 mg to 1.0 g of trigonelline per kg of human body weight.

[0127] In some embodiments, at least a portion of the trigonelline is isolated. Additionally or alternatively, at least a portion of the trigonelline can be chemically synthesized.

[0128] In one embodiment, the composition comprises at least about 90% of the chemically synthesized trigonelline, preferably at least about 98% of the trigonelline.

[0129] In preferred embodiments, at least a portion of trigonelline is provided by a plant or algal extract, for example from an extract from one or more of coffee beans (e.g., green coffee extract), Japanese radish, fenugreek seed, pea, hemp seed, oat, potato, gazania, Stachys species, Strophanthus species, Laminariaceae species (especially Laminaria and Saccharina), Postelsia palmaeformis, Pseudochorda nagaii, Akkesiphycus, or Dichapetalum cymosum. The plant extract is preferably enriched for trigonelline, i.e., the starting plant material comprises one or more other compounds in addition to trigonelline, and the enriched plant material has a higher ratio of trigonelline relative to at least one of the one or more other compounds than in the starting plant material.

[0130] Accordingly, some embodiments of the composition comprise a plant source and / or an enriched plant source that provides at least a portion of the trigonelline in the composition.

[0131] In preferred embodiments, the composition comprises an enriched fenugreek extract that provides at least about 25% to 50% of the trigonelline in the composition. In more preferred embodiments, the composition comprises an enriched fenugreek extract that provides at least about 28% to 40% of the trigonelline.

[0132] In each of the compositions and methods disclosed herein, the composition is preferably a food product, including a food additive, a food ingredient, a functional food, a dietary supplement, a medical food, a nutraceutical, an oral nutritional supplement (ONS), or a food supplement.

[0133] 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), and most preferably at least five days per week, six days per week, or seven days per week. The period of administration can be at least one week, preferably at least one month, more preferably at least two months, and most preferably at least three months, e.g., at least four months. In some embodiments, the administration is taken at least daily; for example, the individual can receive one or more doses per day, in embodiments multiple doses per day. In some embodiments, the administration is continued for the remainder of the individual’s life. In other embodiments, the administration is continued until the detectable symptoms of the medical condition have resolved. In specific embodiments, the administration is continued until at least one symptom has detectably improved, and in additional cases the administration is continued to maintain remission.

[0134] In some embodiments, trigonelline is 0.1% to 80% by weight of the composition, for example 0.1% to 60% by weight of the composition, such as 0.25% to 50% by weight of the composition, 0.5% to 50% by weight of the composition. If the composition is provided as a part or all of a meal, the urolithins can be 0.25% to 5% by weight of the composition, for example 0.3% to 3% by weight of the composition. If the composition is provided as a single serving supplement to an individual’s daily diet, the urolithins can be 20% to 80% w / w of the composition, for example 20% to 40% of the composition, for example 25% to 35% of the composition.

[0135] 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 100 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 throughout the hours of the day. However, the amount of compound and / or composition administered in any given case will depend on such factors as the solubility of the active ingredient, the formulation employed, the individual’s condition, such as body weight, and / or the route of administration. For example, the daily doses of trigonelline disclosed above are non-limiting and, in some embodiments, can be different; in particular, the compositions comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof as disclosed herein can be used as a special medical purpose food (FSMP) for acute phase care and contain up to about 100 mg of trigonelline per day.

[0136] In one embodiment, the administration of the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof can be for at least about 2 months or 3 months, preferably at least about 4 months or 5 months, more preferably at least about 6 months or 7 months, such as about 2 months to 60 months, 2 months to 48 months, 2 months to 36 months, 2 months to 24 months or 2 months to 12 months, preferably such as about 4 months to 60 months, 4 months to 48 months, 4 months to 36 months, 4 months to 24 months or 4 months to 12 months, etc. in the remission phase.

[0137] In another embodiment, the composition comprising trigonelline or 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 slow progression of glomerular filtration rate (GFR) and / or to reduce glomerular hyaline lesions and / or to increase lean body mass of muscle.

[0138] In another embodiment, the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is administered for 5 weeks to slow progression of glomerular filtration rate (GFR) and / or to reduce glomerular hyaline lesions and / or to increase lean body mass of muscle.

[0139] In another embodiment, an amount of the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is administered for 10 weeks to increase lean body mass of muscle and / or to increase muscle fiber size and / or to increase levels of at least one nicotinamide adenine dinucleotide.

[0140] The composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof as disclosed herein can be used in any of a variety of formulations for therapeutic administration. More specifically, the pharmaceutical composition can comprise an appropriate pharmaceutically acceptable carrier or diluent and can 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. Thus, 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, can be systemic after administration, or can be localized by the use of regional administration, intramural administration, or the use of an implant that acts to retain the active agent amount at the site of implantation.

[0141] In one embodiment, the composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof is administered enterally.

[0142] 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 produce tablets, powders, granules, or capsules, e.g., in combination with conventional additives, such as lactose, mannitol, corn starch, or potato starch; binding agents, such as crystalline cellulose, cellulose functional derivatives, acacia, corn starch, or gelatin; disintegrating agents, such as corn starch, potato starch, or sodium carboxymethyl cellulose; lubricating agents, such as talc or magnesium stearate; and, if desired, diluents, buffering, moistening, or preservative agents, color- ing agents, flavoring agents, and sweetening agents.

[0143] The composition comprising trigonelline or trigonelline or its pharmaceutically acceptable salt can be used in an aerosol formulation for administration by inhalation. For example, the composition comprising trigonelline or trigonelline or its pharmaceutically acceptable salt can be formulated in a pressurized acceptable propellant, such as dichlorodifluoromethane, propane, nitrogen and the like.

[0144] Further, the composition comprising trigonelline or trigonelline or its pharmaceutically acceptable salt can be made into a suppository by mixing with a variety of vehicles such as an emulsifying base or a water-soluble base. The composition comprising trigonelline or trigonelline or its pharmaceutically acceptable salt can be administered rectally by a suppository. The suppository can comprise vehicles such as cocoa butter, carbowax and polyethylene glycol, which melt at body temperature, but which solidify in room temperature.

[0145] Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions can be provided, wherein each dosage unit (e.g., teaspoonful, tablespoonful, tablet or suppository) contains a predetermined amount of the composition comprising trigonelline or trigonelline or its pharmaceutically acceptable salt.

[0146] In another embodiment, the composition comprising trigonelline or trigonelline or its pharmaceutically acceptable salt is administered parenterally. Non-limiting examples of parenteral administration include intravenous, intramuscular, intraperitoneal, subcutaneous, intra-articular, intrasynovial, intraocular, intrathecal, topical, and inhalation. Thus, non-limiting examples of forms of the composition comprising trigonelline or trigonelline or its pharmaceutically acceptable salt include natural foods, processed foods, natural juices, concentrates and extracts, injectable solutions, microcapsules, nanocapsules, liposomes, plasters, inhalation forms, nasal sprays, nose drops, eye drops, sublingual tablets, and sustained release formulations.

[0147] Unit dosage forms for injection or intravenous administration can comprise the composition comprising trigonelline or trigonelline or its pharmaceutically acceptable salt in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier, wherein each dosage unit (e.g., mL or L) contains a predetermined amount of the composition comprising trigonelline or trigonelline or its pharmaceutically acceptable salt.

[0148] Compositions intended for non-human animals include food compositions that provide the necessary dietary / meal requirements for the animal, animal treat foods (e.g., biscuits), and / or dietary supplements. The compositions can be dry compositions (e.g., kibbles), semi-moist compositions, wet compositions, 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 include high concentrations of UFAs and NORCs, as well as B-vitamins and antioxidants. This allows the supplement to be administered to the animal in small amounts, or in the alternative can be diluted prior to administration to the animal. The dietary supplement can need to be admixed, or can be admixed with water or other diluent prior to administration to the animal.

[0149] A pet food or pet treat food composition includes about 15% to about 50% crude protein. The crude protein material can include 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 proteins. Examples of meat proteins that can be used in the present application include pork, lamb, horse meat, poultry meat, fish meat, and mixtures thereof. The composition can also include about 5% to about 40% fat. The composition can also include a source of carbohydrate. The composition can include about 15% to about 60% carbohydrate. Examples of such carbohydrates include grains or cereals, such as rice, corn, sorghum, milo, alfalfa, barley, soybean, rapeseed, oat, wheat, and mixtures thereof. The composition can also optionally include other materials, such as whey powder and other dairy by-products.

[0150] In some embodiments, the pet food composition has an ash content in the range of less than 1% to about 15%, and in one aspect, about 5% to about 10%.

[0151] The moisture content can vary depending on the nature of the pet food composition. In one embodiment, the composition can be a nutritionally complete pet food. In this embodiment, the pet food can be a "wet food," a "dry food," or a food of intermediate moisture content. "Wet food" describes pet food that is typically sold in cans or foil pouches and has a moisture content that is typically in the range of about 70% to about 90%. "Dry food" describes pet food that is similar in composition to wet food, but has a limited moisture content, typically in the range of about 5% to about 15% or 20%, and thus appears as, for example, small biscuit-like kibbles. In one embodiment, the composition has a moisture content of about 5% to about 20%. Dry food products include a variety of foods having various moisture contents, such that they are relatively shelf-stable and resistant to microbial or fungal spoilage or contamination. Dry food compositions that are extruded food products are also included, such as pet food or companion animal treats.

[0152] In another aspect, the present disclosure provides a method of increasing muscle stem cells and / or reducing muscle stem cell decline in an individual having diabetes, the method comprising administering to the individual having diabetes an effective amount of trigonelline or a pharmaceutically acceptable salt thereof. The muscle can be tibialis anterior muscle and / or extensor digitorum longus (EDL) and / or soleus muscle. Preferably, the trigonelline or the pharmaceutically acceptable salt thereof is administered enterally or parenterally. The trigonelline or the pharmaceutically acceptable salt thereof can 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 milk-based drink, a low-volume liquid supplement, a meal replacement beverage, and combinations thereof. Preferably, the trigonelline or the pharmaceutically acceptable salt thereof is micronized.

[0153] Examples

[0154] Example 1

[0155] The following non-limiting examples discuss experimental data that were investigated to further support the methods and compositions disclosed herein.

[0156] The kidney protective effect of trigonelline was evaluated in a mouse model of type 2 diabetes (db / db mice).

[0157] A mouse model of diabetes, db / db mice, certified by the Diabetes Complications Consortium (DiabComp / AMDCC), which are obese and insulin resistant "type 2". This mouse model has been shown to have decreased NAD+ levels in the kidney.

[0158] To obtain a reasonably large cohort to run groups in series, which is essential for a reliable test of renal function, mice were purchased from Charles River (JAX Laboratory, USA). Seven-week-old male db / db mice (n = 8-10 / group) received trigonelline by food administration (300 mg / kg / day) for 8 weeks. Db / m (control), db / db (diabetic), and db / db (diabetic + dapagliflozin ("dapa"), 10 mg / kg / day by gavage) mice were randomly assigned to the following treatments:

[0159]

[0160] Animals used were 8 db / m and 20 db / db, obtained from Charles River (JAX Laboratory, USA). Mice had free access to tap water and standard rodent maintenance chow. All mice were kept in a room with constant temperature of approximately 25°C, 12h light / dark cycle.

[0161] Fresh urine samples were collected from each animal prior to glomerular filtration rate (GFR) measurement at baseline, midpoint, and one week prior to euthanasia. Briefly, animals were housed individually in cages without bedding until collection of fresh urine samples was completed. The volume of urine collected was placed in a 2 mL tube and immediately stored at -80°C.

[0162] All analyses were performed by ANOVA followed by post-hoc pairwise analysis using the Tukey's least significant difference method while correcting for multiple comparisons. A p-value < 0.05 was considered statistically significant. Z-score of 2 was used to exclude outliers.

[0163] Whole body composition, including lean mass and fat mass, was measured at baseline, midpoint, and endpoint using EchoMRI. Overall, db / db mice (diabetic) had increased fat mass and total body weight, and decreased lean mass when compared to db / m (control), independent of treatment. Lean mass was significantly increased in the db / db + trigonelline group when compared to the db / db + V group (diabetic). Results are shown in Figure 1 Specifically, the tibialis anterior, quadriceps, and soleus muscles showed a significant increase in muscle mass in the db / db + trigonelline (TG) group when compared to the db / db + V group (diabetic). Results are shown in Figure 2a , Figure 2b and in Figure 2C.

[0164] Fiber size distribution and fiber number were measured on the tibialis anterior muscle after 8 weeks of treatment with trigonelline, administered at 300 mg / kg / day (+TG, db / db + trigonelline group), and compared to the vehicle group maintained on chow for 8 weeks (Diabetic, db / db + V group) and the control group (Control, db / m + V group)

[0165] The measurement of fiber size distribution and fiber number was performed after cryosectioning of the tibialis anterior muscle, staining of laminin and muscle nuclei. All sections were acquired with an Olympus VS120 slide scanning microscope. The size of muscle fibers was calculated using the minimum Feret diameter with an automated image processing algorithm developed in-house using QuPath software and the Fiji tool open-CSAM. Results are shown in Figure 3 and Figure 4 .

[0166] GFR progression was measured at baseline, midpoint and endpoint with a transdermal monitoring device. FITC-phalloidin (50 mg / kg) was administered via the tail vein. GFR was recorded for 1.5 hours. At the end of the recording period, the transdermal GFR monitoring device was removed and read. Then, data were analyzed according to the manufacturer recommendations using a dedicated software. GFR progression was measured between the midpoint and the endpoint after 8 weeks of treatment with trigonelline, administered at 300 mg / kg / day (+TG, db / db + trigonelline group), and compared to the vehicle group maintained on chow for 8 weeks (Diabetic, db / db + V group), the control group (Control, db / m + V group) and the dapa group (Diabetic, db / db + dapa group), Figure 5 .

[0167] Hyalinosis was measured after 8 weeks of treatment with trigonelline, administered at 300 mg / kg / day (+TG, db / db + trigonelline group), and compared to the vehicle group maintained on chow for 8 weeks (Diabetic, db / db + V group), the control group (Control, db / m + V group) and the dapa group (dapa, db / db + dapa group), Figure 6 wherein hyalinosis refers to the thickening of the wall of the glomerular arteriole due to deposition of homogeneous glassy material, which was measured using a scoring system as no injury, moderate injury or severe injury.

[0168] Kidney NAD+ levels were measured in mice after 8 weeks of treatment with trigonelline, administered at 300 mg / kg / day (+trigonelline, db / db + trigonelline group), and compared to the vehicle group (Diabetic, db / db + V group), the control group (Healthy, db / m + V group) and the dapa group (Diabetic, db / db + dapa group). Kidney NAD+ levels were measured using the NAD / NADH kit,Figure 7 .

[0169] Example 2

[0170] The following non-limiting examples discuss experimental data that were investigated to further support the methods and compositions disclosed herein.

[0171] Frozen tibialis anterior muscles were cut into 10 pm sections using a cryostat (Leica Biosystems). For Pax7 staining, sections were fixed with 4% PFA and permeabilized in cold methanol. Next, sections were co-incubated with primary antibody anti-Pax7 and Hoechst 33342 for nuclei detection. Then, sections were 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 Pax7 positive cells was determined by manual counting across the muscle section.

[0172] As shown in Figure 8 , after 8 weeks of treatment at 300 mg / kg / day, trigonelline increased the number of muscle stem cells in the tibialis anterior muscle of mice. (+ Trigonelline, diabetic + Tg group) compared to the vehicle group (diabetic group), control group (healthy, non-diabetic group). Specifically, the number of muscle stem cells quantified by the Pax7 marker in the muscle was reduced in the diabetic group compared to the healthy group, and trigonelline significantly rescued this number.

Claims

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

2. The method of claim 1, wherein 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 an 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 wasting and / or the renal dysfunction is treated and / or prevented in early chronic kidney disease and / or in late chronic kidney disease.

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

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 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 milk-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 outcome selected from the group consisting of (i) slowing progression of glomerular filtration rate (GFR); (ii) reducing glomerular hyalinosis lesions in an individual in need thereof, the method comprising administering to the individual in need thereof an effective amount of a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof.

10. The method of claim 9, wherein the individual has a disease or condition 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 an 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 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 milk-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 outcome selected from the group consisting of: (i) increasing lean body mass of muscle; (ii) increasing muscle fiber size; (iii) increasing levels of at least one nicotinamide adenine dinucleotide in muscle in an individual in need thereof, comprising administering to the individual in need thereof an effective amount of a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof.

16. The method of claim 15, wherein the individual has a disease or condition selected from the group consisting of: chronic kidney disease, metabolic-induced muscle wasting, end-stage renal disease, dialysis, diabetes, muscle loss and / or renal failure due to hospitalization in an 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 body mass of muscle is increased in early chronic kidney disease and / or in late chronic kidney disease.

18. The method of claim 15, wherein the muscle is tibialis anterior muscle 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 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 milk-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 the treatment and / or prevention of a disease or condition associated with muscle decline and / or kidney dysfunction, comprising a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof; preferably the nutritional composition comprises an amount of trigonelline effective to treat and / or prevent a disease or condition associated with muscle decline and / or kidney dysfunction in an individual in need thereof.

27. The composition of claim 26, comprising an amount of trigonelline effective to slow progression of glomerular filtration rate (GFR) and / or reduce glomerular hyaline lesions and / or increase lean body mass of muscle.

28. The composition of claim 26, comprising an amount of trigonelline effective to increase lean body mass of muscle and / or increase muscle fiber size.

29. The composition of claim 26, comprising an amount of trigonelline effective to increase levels 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.

31. The composition of claim 26, selected from the group consisting of a food product, a food for special medical purposes (FSMP), a nutritional supplement, a milk-based 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 the treatment and / or prevention of a disease or condition associated with muscle decline and / or kidney dysfunction, comprising a composition comprising trigonelline or trigonelline or a pharmaceutically acceptable salt thereof; preferably the unit dosage form comprises an amount of trigonelline effective to treat and / or prevent a disease or condition associated with muscle decline and / or kidney dysfunction in an individual in need thereof.

35. The unit dosage form of claim 34, comprising an amount of trigonelline effective to slow progression of glomerular filtration rate (GFR) and / or reduce glomerular hyaline lesions and / or increase lean body mass of muscle.

36. The unit dosage form of claim 34, comprising an amount of trigonelline effective to increase lean body mass of muscle and / or increase muscle fiber size.

37. The unit dosage form of claim 34, comprising an amount of trigonelline effective to increase levels 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.

39. The unit dosage form of claim 34, selected from the group consisting of a food product, a food for special medical purposes (FSMP), a nutritional supplement, a milk-based 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 reducing muscle stem cell decline in an individual having diabetes, the method comprising administering to the individual 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.

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 milk-based 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.

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