Method for enhancing or improving muscle functions and improving athletic performance and / or preventing or relieving fatigue, and composition

Abstract

A method for enhancing or improving muscle functions and / or improving athletic performance and / or preventing or relieving fatigue and / or increasing or improving a nitric oxide signal or level, comprising: administering a citrulline dipeptide or a salt, ester, and derivative thereof to a subject.

Description

Methods and compositions for enhancing or improving muscle function and increasing athletic performance and / or preventing or alleviating fatigue TECHNICAL FIELD

[0001] The present invention belongs to the technical field of nutritional products or dietary supplements, in particular relates to a method and composition for enhancing or improving muscle function and / or increasing athletic performance and / or preventing or alleviating fatigue. BACKGROUND

[0002] It is well known that exercise has many benefits, such as improving the quality of life, optimizing heart and blood vessel health, controlling blood pressure, optimizing brain health and memory, increasing happiness, strengthening bones and muscles, reducing joint stiffness, reducing the risk of falling, optimizing sleep quality, etc. In addition, exercise has a positive effect on muscle strength and overall muscle tone. A study concluded that exercise has a moderate to major impact on muscle strength, body composition, physiological function, and inflammatory response in older adults. Therefore, it is crucial to improve athletic performance and muscle function.

[0003] In order to improve athletic performance, many people who exercise and lift weights regularly choose to take supplements. However, the current products have many side effects (such as palpitations, rapid heartbeat, etc.) and are not effective enough. Therefore, it is crucial to find a product that is efficient and has no side effects.

[0004] Nitric oxide (NO), also known as nitrogen oxide, is produced by almost every cell in the human body. It is believed to be a mediator of intercellular communication and plays an important role in various processes in the body, including inflammation, vasodilation, and neurotransmission. First of all, when it comes to our vascular health, it is considered one of the most important molecules. For example, NO plays a very crucial role in vasodilation and can also lower blood pressure. NO is a signaling molecule that is widely present in the cardiovascular system and various cell types, and prevents the occurrence and development of atherosclerosis in multiple ways. In simple terms, NO can improve endothelial function. NO also has the effect of scavenging oxygen free radicals, including preventing the oxidation of low-density lipoprotein cholesterol. NO can regulate the central nervous system and improve neurodegeneration. NO can also improve tolerance to aerobic and anaerobic exercise. NO plays an important regulatory role in skeletal muscle glucose uptake during contraction / exercise. Therefore, it is particularly important to enhance the signal of NO.

[0005] Currently, products on the market that enhance the signal of NO can have side effects such as nausea, stomach upset, and palpitations, etc. Therefore, it is crucial to find a product that can enhance the signal of NO without side effects. SUMMARY

[0006] One aspect of the present application relates to a method of enhancing or improving muscle function and / or improving athletic performance and / or preventing or alleviating fatigue and / or increasing or improving nitric oxide signaling or levels, the method comprising: administering to a subject a citrulline dipeptide or a salt, ester, derivative thereof. In some embodiments, an effective amount of a citrulline dipeptide or a salt, ester, derivative thereof is administered to a subject.

[0007] In some embodiments, enhancing or improving muscle function comprises one or more of: alleviating or preventing muscle dysfunction, improving mitochondrial function in muscle, improving insulin resistance in muscle, increasing muscle mass, increasing the number of muscle fibers, increasing muscle strength and endurance, increasing skeletal muscle glucose transport, metabolism, alleviating or preventing muscle damage, and reducing muscle fatigue; improving athletic performance comprises one or more of: increasing running and / or swimming distance, increasing exercise time, increasing running and / or swimming speed, increasing exercise endurance or power, reducing post-exercise inflammation and muscle fatigue, improving muscle contraction during exercise; preventing or alleviating fatigue comprises preventing post-exercise physical fatigue, accelerating post-exercise recovery.

[0008] In some embodiments, the method can reduce lactic acid accumulation, or maintain or elevate muscle glycogen content, or maintain or reduce urea nitrogen content, and / or increase or elevate nitrite and / or cyclic guanosine monophosphate levels.

[0009] In some embodiments, the method enhances or improves muscle function and / or improves athletic performance and / or prevents or alleviates fatigue by increasing the level or signaling of nitric oxide, or increasing the level of cyclic guanosine monophosphate (cGMP), or increasing the level of nitrite.

[0010] In some embodiments, the method further comprises: administering to the subject an arginine dipeptide or a salt, ester, derivative thereof.

[0011] In some embodiments, the weight ratio of the arginine dipeptide or a salt, ester, derivative thereof to the citrulline dipeptide or a salt, ester, derivative thereof is 1:50 to 50:1. In some embodiments, the weight ratio of the arginine dipeptide or a salt, ester, derivative thereof to the citrulline dipeptide or a salt, ester, derivative thereof is 1:25 to 25:1. In some embodiments, the weight ratio of the arginine dipeptide or a salt, ester, derivative thereof to the citrulline dipeptide or a salt, ester, derivative thereof can be 1:40 to 40:1, 1:30 to 30:1, 1:20 to 20:1, 1:15 to 15:1, 1:12 to 12:1, 1:10 to 10:1, 1:8 to 8:1, 1:5 to 5:1, 1:3 to 3:1, 1:1.

[0012] In some embodiments, muscle function or performance of the subjects of the administration group is increased or improved and / or fatigue is prevented or alleviated by greater than 10%, 30%, 40%, 50%, 60%, 70%, or 90% and the nitric oxide signal or level of the administration group of subjects is increased or improved by greater than 10%, 30%, 40%, 50%, 60%, 70%, 90%, 120%, 150%, or 180% relative to subjects who do not receive the administration.

[0013] In some embodiments, the exercise time of the administration group is increased by greater than 10%, 30%, 45%, or 50% relative to the exercise group that does not receive the administration. The running distance of the administration group is increased by greater than 10%, 20%, 30%, 35%, or 50% relative to the exercise group that does not receive the administration. The serum lactate level of the administration group is decreased by greater than 10%, 15%, or 20% relative to the exercise group that does not receive the administration. The liver glycogen level of the administration group is increased by greater than 20%, 30%, or 40% relative to the exercise group that does not receive the administration.

[0014] In some embodiments, the subject is a human or a mammal.

[0015] In some embodiments, the citrulline dipeptide or its salt, ester, derivative, or mixture thereof with arginine dipeptide or its salt, ester, derivative can be formulated into a nutritional product, a dietary supplement, a food, a beverage, or an animal feed. In some embodiments, the citrulline dipeptide or its salt, ester, derivative, or mixture thereof with arginine dipeptide or its salt, ester, derivative is prepared into a solid formulation or a liquid formulation.

[0016] In some embodiments, the citrulline dipeptide or its salt, ester, derivative, or mixture thereof with arginine dipeptide or its salt, ester, derivative is in the form of a lotion, a paste, a suppository, a tablet, a pill, a granule, a powder, a film, a capsule, a beverage, an aerosol, a spirit, a tincture, a tonic, a liquid suspension, a syrup.

[0017] In some embodiments, the administration dose of the citrulline dipeptide or its salt, ester, derivative is 0.1 μΜ to 1 M or 0.1-30 g or 0.001 to 90.0% (w / w). The administration dose of the arginine dipeptide or its salt, ester, derivative is 0.1 μΜ to 1 M or 0.1-30 g or 0.001 to 90.0% (w / w).

[0018] In some embodiments, the citrulline dipeptide or its salt, ester, derivative, or mixture thereof with arginine dipeptide or its salt, ester, derivative can be administered before exercise, during exercise, or after exercise.

[0019] In some embodiments, the composition is administered at least once a day for 1 week to 7 weeks, 2 weeks to 7 weeks, 3 weeks to 7 weeks, 4 weeks to 7 weeks.

[0020] In some embodiments, the present methods include oral, intravenous, intramuscular, intraperitoneal, topical instillation, external, or sublingual administration, among other routes. The citrulline dipeptide or salt, ester, derivative thereof, or mixture thereof with an arginine dipeptide or salt, ester, derivative thereof is administered in a single dose or in multiple divided doses, with a daily dose ranging from 0.1 g to 30 g, 0.5 g to 30 g, 0.5 g to 25 g, 0.5 g to 20 g, 1 g to 30 g, 1 g to 28 g, 1 g to 25 g, 1 g to 20 g. In some embodiments, the daily dose ranges from 0.005% to 90%, 0.01% to 85%, 0.05% to 80%, 0.05% to 80%, 0.5% to 75%, 1% to 70%, 2% to 50%, 0.005% to 45%, 0.005% to 40%, 0.005% to 30%, 0.005% to 25%, 0.01% to 40%, 0.01% to 30%, 0.01% to 25%, 0.01% to 15%, 0.05% to 30%, 0.05% to 20%, 0.05% to 10%, 0.1% to 35%, 0.1% to 25%, 0.1% to 10%, 0.2% to 25%, 0.2% to 10%, 0.5% to 9%, 1% to 7%, 2% to 7%, 0.005% to 7%, 0.005% to 9% (w / w). In some embodiments, the daily dose ranges from 0.1 μΜ to 1 M (e.g., 0.1 μΜ to 500 μΜ, 1 μΜ to 500 μΜ, 1 μΜ to 5 mM, 1 μΜ to 500 mM, 5 μΜ to 500 μΜ, 5 μΜ to 5 mM, 5 μΜ to 100 mM, 5 μΜ to 500 mM, 50 μΜ to 500 μΜ, 50 μΜ to 5 mM).

[0021] In some embodiments, the method further comprises administering a component that increases nitric oxide signaling or levels, the component being coenzyme Q10, vitamin E, vitamin C, carnosine, lycopene, creatine, arginine, cysteine, resveratrol, taurine, ergothioneine, glutathione, and / or citrulline and salts thereof.

[0022] Another aspect of the present application relates to the use of a citrulline dipeptide or salt, ester, derivative thereof in the manufacture of a composition for enhancing or improving muscle function and / or increasing athletic performance and / or preventing or alleviating fatigue and / or increasing or improving nitric oxide signaling or levels.

[0023] In some embodiments, enhancing or improving muscle function includes one or more of: alleviating or preventing muscle dysfunction, improving mitochondrial function in muscle, improving insulin resistance in muscle, increasing muscle mass, increasing the number of muscle fibers, increasing muscle strength and endurance, increasing glucose transport, metabolism in skeletal muscle, alleviating or preventing muscle damage, and reducing muscle fatigue; improving athletic performance includes one or more of: increasing distance of running and / or swimming, increasing time of exercise, increasing speed of running and / or swimming, increasing exercise endurance or explosive power, reducing post-exercise inflammation and muscle fatigue, improving muscle contraction during exercise; preventing or alleviating fatigue includes preventing post-exercise physical fatigue, accelerating post-exercise recovery.

[0024] In some embodiments, the composition can reduce lactic acid accumulation, or maintain or increase muscle glycogen content, or maintain or decrease urea nitrogen content, and / or increase or improve levels of nitrite and / or cyclic guanosine monophosphate.

[0025] In some embodiments, muscle function is enhanced or improved and / or athletic performance is improved and / or fatigue is prevented or alleviated by increasing levels or signaling of nitric oxide, or increasing levels of cyclic guanosine monophosphate (cGMP), or increasing levels of nitrite.

[0026] In some embodiments, the composition further comprises: an arginine dipeptide or a salt, ester, derivative thereof.

[0027] In some embodiments, the weight ratio of the arginine dipeptide or a salt, ester, derivative thereof to the citrulline dipeptide or a salt, ester, derivative thereof is 1:50 to 50:1. In some embodiments, the weight ratio of the arginine dipeptide or a salt, ester, derivative thereof to the citrulline dipeptide or a salt, ester, derivative thereof is 1:25 to 25:1. In some embodiments, the weight ratio of the arginine dipeptide or a salt, ester, derivative thereof to the citrulline dipeptide or a salt, ester, derivative thereof can be 1:40 to 40:1, 1:30 to 30:1, 1:20 to 20:1, 1:15 to 15:1, 1:12 to 12:1, 1:10 to 10:1, 1:8 to 8:1, 1:5 to 5:1, 1:3 to 3:1, 1:1.

[0028] In some embodiments, muscle function or athletic performance is increased or improved and / or fatigue is prevented or alleviated by greater than 10%, 30%, 40%, 50%, 60%, 70%, or 90% and / or nitric oxide signaling or levels are increased or improved by greater than 10%, 30%, 40%, 50%, 60%, 70%, 90%, 120%, 150%, or 180% in a subject administered the composition relative to a subject not receiving the composition.

[0029] In some embodiments, the citrulline dipeptide or its salts, esters, derivatives or mixtures thereof with arginine dipeptide or its salts, esters, derivatives are prepared into solid formulations or liquid formulations.

[0030] In some embodiments, the citrulline dipeptide or its salts, esters, derivatives or mixtures thereof with arginine dipeptide or its salts, esters, derivatives are in the form of a lotion, paste, suppository, tablet, pill, granule, powder, film, capsule, beverage, aerosol, spirit, tincture, tonic, liquid suspension, syrup.

[0031] In some embodiments, the citrulline dipeptide or its salts, esters, derivatives or mixtures thereof with arginine dipeptide or its salts, esters, derivatives are administered at a dose of 0.1 μΜ to 1 M or 0.1-30 g or 0.001 to 90.0% (w / w). The arginine dipeptide or its salts, esters, derivatives are administered at a dose of 0.1 μΜ to 1 M or 0.1-30 g or 0.001 to 90.0% (w / w).

[0032] In some embodiments, the citrulline dipeptide or its salts, esters, derivatives or mixtures thereof with arginine dipeptide or its salts, esters, derivatives are administered by a single dose or multiple divided doses, with a daily dose ranging from 0.1 g to 30 g, 0.5 g to 30 g, 0.5 g to 25 g, 0.5 g to 20 g, 1 g to 30 g, 1 g to 28 g, 1 g to 25 g, 1 g to 20 g. In some embodiments, the daily dose ranges from 0.005% to 90%, 0.01% to 85%, 0.05% to 80%, 0.05% to 80%, 0.5% to 75%, 1% to 70%, 2% to 50%, 0.005% to 45%, 0.005% to 40%, 0.005% to 30%, 0.005% to 25%, 0.01% to 40%, 0.01% to 30%, 0.01% to 25%, 0.01% to 15%, 0.05% to 30%, 0.05% to 20%, 0.05% to 10%, 0.1% to 35%, 0.1% to 25%, 0.1% to 10%, 0.2% to 25%, 0.2% to 10%, 0.5% to 9%, 1% to 7%, 2% to 7%, 0.005% to 7%, 0.005% to 9% (w / w). In some embodiments, the daily dose ranges from 0.1 μΜ to 1 M (e.g., 0.1 μΜ to 500 μΜ, 1 μΜ to 500 μΜ, 1 μΜ to 5 mM, 1 μΜ to 500 mM, 5 μΜ to 500 μΜ, 5 μΜ to 5 mM, 5 μΜ to 100 mM, 5 μΜ to 500 mM, 50 μΜ to 500 μΜ, 50 μΜ to 5 mM).

[0033] Another aspect of the present application relates to a composition comprising an arginine dipeptide or a salt, ester, derivative thereof, and a citrulline dipeptide or a salt, ester, derivative thereof.

[0034] In some embodiments, the composition is used to enhance or improve muscle function and / or to improve athletic performance and / or to prevent or alleviate fatigue and / or to increase or improve nitric oxide signaling or levels in a subject.

[0035] In some embodiments, enhancing or improving muscle function comprises one or more of the following: alleviating or preventing muscle dysfunction, improving mitochondrial function in muscle, improving insulin resistance in muscle, increasing muscle mass, increasing the number of muscle fibers, increasing muscle strength and endurance, increasing skeletal muscle glucose transport, metabolism, alleviating or preventing muscle damage, and reducing muscle fatigue; improving athletic performance comprises one or more of the following: increasing running and / or swimming distance, increasing exercise time, increasing running and / or swimming speed, increasing exercise endurance or power, reducing post-exercise inflammation and muscle fatigue, improving muscle contraction during exercise; preventing or alleviating fatigue comprises preventing post-exercise physical fatigue, accelerating post-exercise recovery.

[0036] In some embodiments, the composition can reduce lactic acid accumulation, or maintain or elevate muscle glycogen content, or maintain or reduce urea nitrogen content, and / or increase or elevate nitrite and / or cyclic guanosine monophosphate levels.

[0037] In some embodiments, the composition enhances or improves muscle function and / or improves athletic performance and / or prevents or alleviates fatigue by increasing levels or signaling of nitric oxide, or increasing levels of cyclic guanosine monophosphate (cGMP), or increasing levels of nitrite.

[0038] In some embodiments, the weight ratio of the arginine dipeptide or a salt, ester, derivative thereof to the citrulline dipeptide or a salt, ester, derivative thereof is 1:50 to 50:1. In some embodiments, the weight ratio of the arginine dipeptide or a salt, ester, derivative thereof to the citrulline dipeptide or a salt, ester, derivative thereof is 1:25 to 25:1. In some embodiments, the weight ratio of the arginine dipeptide or a salt, ester, derivative thereof to the citrulline dipeptide or a salt, ester, derivative thereof can be 1:40 to 40:1, 1:30 to 30:1, 1:20 to 20:1, 1:15 to 15:1, 1:12 to 12:1, 1:10 to 10:1, 1:8 to 8:1, 1:5 to 5:1, 1:3 to 3:1, 1:1.

[0039] In some embodiments, the muscle function or performance of the subject administered the composition is increased or improved and / or fatigue is prevented or alleviated by greater than 10%, 30%, 40%, 50%, 60%, 70%, or 90% and / or the nitric oxide signal or level of the subject administered the composition is increased or improved by greater than 10%, 30%, 40%, 50%, 60%, 70%, 90%, 120%, 150%, or 180% relative to a subject that does not receive the administration.

[0040] In some embodiments, the composition is in the form of a lotion, paste, suppository, tablet, pill, granule, powder, film, capsule, beverage, aerosol, spirit, tincture, tonic, liquid suspension, syrup.

[0041] In some embodiments, the amount of the composition is 0.1 μΜ to 1 M or 0.1-30 g or 0.001 to 90.0% (w / w).

[0042] Another aspect of the present application relates to a method of increasing or improving the level of nitrite and / or cyclic guanosine monophosphate, the method comprising: administering to a subject a citrulline dipeptide or a salt, ester, derivative thereof. In some embodiments, an effective amount of the citrulline dipeptide or a salt, ester, derivative thereof is administered to the subject.

[0043] In some embodiments, the method further comprises: administering to the subject an arginine dipeptide or a salt, ester, derivative thereof.

[0044] In some embodiments, the weight ratio of the arginine dipeptide or a salt, ester, derivative thereof to the citrulline dipeptide or a salt, ester, derivative thereof is 1:50 to 50:1.

[0045] In some embodiments, the level of nitrite and / or cyclic guanosine monophosphate of the subject administered is increased or improved by greater than 10%, 30%, 40%, 50%, 60%, 70%, or 90% relative to a control subject that does not receive the administration.

[0046] In some embodiments, the subject is a human or a mammal.

[0047] In some embodiments, the citrulline dipeptide or a salt, ester, derivative thereof or a mixture thereof with the arginine dipeptide or a salt, ester, derivative thereof is formulated into a nutraceutical, a dietary supplement, a food, a beverage, or an animal feed.

[0048] In some embodiments, the citrulline dipeptide or a salt, ester, derivative thereof or a mixture thereof with the arginine dipeptide or a salt, ester, derivative thereof is prepared into a solid formulation or a liquid formulation.

[0049] In some embodiments, the citrulline dipeptide or its salts, esters, derivatives or mixtures thereof with arginine dipeptide or its salts, esters, derivatives are in the form of a lotion, paste, suppository, tablet, pill, granule, powder, film, capsule, beverage, aerosol, spirit, tincture, tonic, liquid suspension, syrup.

[0050] In some embodiments, the citrulline dipeptide or its salts, esters, derivatives is administered at a dose of 0.1 μΜ to 1 M or 0.1-30 g or 0.001 to 90.0% (w / w). The arginine dipeptide or its salts, esters, derivatives is administered at a dose of 0.1 μΜ to 1 M or 0.1-30 g or 0.001 to 90.0% (w / w).

[0051] Another aspect of the present application also relates to the use of citrulline dipeptide or its salts, esters, derivatives in the manufacture of a composition for increasing or improving the level of nitrite and / or cyclic guanosine monophosphate.

[0052] In some embodiments, the composition further comprises: arginine dipeptide or its salts, esters, derivatives.

[0053] In some embodiments, the weight ratio of arginine dipeptide or its salts, esters, derivatives to the citrulline dipeptide or its salts, esters, derivatives is 1:50 to 50:1.

[0054] In some embodiments, the level of nitrite and / or cyclic guanosine monophosphate of the subject administered with the composition is increased or improved by more than 10%, 30%, 40%, 50%, 60%, 70% or 90% relative to a control subject who does not receive the composition.

[0055] In some embodiments, the citrulline dipeptide or its salts, esters, derivatives is prepared into a solid preparation or a liquid preparation.

[0056] In some embodiments, the citrulline dipeptide or its salts, esters, derivatives or mixtures thereof with arginine dipeptide or its salts, esters, derivatives are in the form of a lotion, paste, suppository, tablet, pill, granule, powder, film, capsule, beverage, aerosol, spirit, tincture, tonic, liquid suspension, syrup.

[0057] In some embodiments, the citrulline dipeptide or its salts, esters, derivatives is administered at a dose of 0.1 μΜ to 1 M or 0.1-30 g or 0.001 to 90.0% (w / w). The arginine dipeptide or its salts, esters, derivatives is administered at a dose of 0.1 μΜ to 1 M or 0.1-30 g or 0.001 to 90.0% (w / w).

[0058] The method of administering citrulline dipeptide or its salt, ester, derivative or mixture or composition comprising the same with arginine dipeptide or its salt, ester, derivative to a subject of the present application can be used to increase or improve muscle function or athletic performance and / or prevent or alleviate fatigue and / or increase or improve nitric oxide signal or level in the subject, which can be used to increase or improve the level of nitrite and / or cyclic guanosine monophosphate, which plays a crucial role in the normal functioning of the cardiovascular, nervous, pulmonary, gastrointestinal, renal and immune systems. BRIEF DESCRIPTION OF DRAWINGS

[0059] Figure 1 is a graph of the body weight changes of six groups of mice during a 28-day feeding intervention.

[0060] Figure 2 is a column chart of the weight-loaded swimming endurance of five groups of mice after a 28-day feeding intervention.

[0061] Figure 3 is a column chart of the treadmill endurance of five groups of mice after a 30-day feeding intervention.

[0062] Figure 4 is a column chart of the serum lactic acid content of six groups of mice after a 35-day feeding intervention.

[0063] Figure 5 is a column chart of the muscle glycogen content of six groups of mice after a 35-day feeding intervention.

[0064] Figure 6 is a column chart of the serum urea nitrogen content of six groups of mice after a 35-day feeding intervention.

[0065] Figure 7 is a graph of the muscle fiber count test results of six groups of mice after a 35-day feeding intervention.

[0066] Figure 8 is a graph of the serum NO concentration of two groups of mice over time.

[0067] Figure 9 is the area under the curve (AUC) of the serum NO content of two groups of mice.

[0068] Figure 10 is a graph of the serum cGMP concentration of two groups of mice over time.

[0069] Figure 11 is the area under the curve (AUC) of the serum cGMP content of two groups of mice.

[0070] Figure 12 is a graph of the NO content test results of three groups of cells. DETAILED DESCRIPTION

[0071] While the application will be described in conjunction with the embodiments, it should be understood that they are not intended to limit the application to these embodiments. On the contrary, the application is intended to cover alternatives, modifications, and equivalents, which can be included within the spirit and scope of the application as defined by the claims. Furthermore, in the detailed description of the application, numerous specific details are set forth in order to provide a thorough understanding of the application. However, it will be apparent to one of ordinary skill in the art that the application can be practiced without these specific details. In other instances, well-known methods, procedures, components, and other features are not described in detail so as not to unnecessarily obscure aspects of the application.

[0072] As used herein, the term "or" is intended to mean "and" and "or". In other words, the term "or" can be replaced by "and / or" in some aspects.

[0073] As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0074] As used herein, the term "comprising" or "including" or variations thereof, means that the items listed after the term encompass not only those items but also items not specifically mentioned. It also includes the more restrictive verbs 'consisting essentially of and 'consisting of.

[0075] As used herein, the term "subject" or "individual" are used interchangeably to refer to any subject to which the methods and compositions of the disclosure can be applied or administered. A subject can have a disease or disorder, but the subject need not be ill in order to benefit from the methods and compositions of the disclosure. Any subject can take the disclosed compositions or be the recipient of the disclosed methods. Herein, the term "subject" refers to an animal (e.g., avian, reptilian, and mammalian). In certain embodiments, the subject can be a mammal including non-primate (e.g., camel, donkey, zebra, cow, horse, cat, dog, rat, and mouse) and primate (e.g., monkey, chimpanzee, human). In certain embodiments, the subject can be a non-human mammal. In other embodiments, the subject can be a human.

[0076] As used herein, the term "administering" refers to the direct administration of a compound or a pharmaceutically acceptable salt of a compound or a composition to a subject, or the administration of a prodrug derivative or analog of a compound or a pharmaceutically acceptable salt of a compound or a composition to a subject, which can form an equivalent amount of the active compound in the subject.

[0077] The contemplated methods include administration of a suitable amount of citrulline dipeptide or salt, ester, derivative thereof or combination thereof with arginine dipeptide or salt, ester, derivative thereof daily, depending on the specific citrulline dipeptide or combination thereof formulation and form. This amount daily can be administered in one or more administrations. Typically, the effective amount of citrulline dipeptide or citrulline dipeptide derivative in a composition of citrulline dipeptide administered one or more times daily is between 0.1 gram (g) and 30 g or between 0.1 gram (g) and 30 g. One or more doses can be administered once daily over any time period. For example, an effective dose can be administered daily for one day, for several days, for many days, or indefinitely daily, the citrulline dipeptide or combination thereof can be administered for 7 days and above in a cycle, depending on the desired effect. More typically, the amount of citrulline dipeptide or citrulline dipeptide derivative or combination thereof composition administered daily is 0.1 g, 0.2 g, 0.3 g, 0.5 g, 0.7 g, 0.9 g, 1 g, 1.2 g, 1.5 g, 3 g, 5 g, 8 g, 10 g, 12 g, 15 g, 18 g, 20 g, 25 g, 30 g. More typically, the amount of citrulline dipeptide or citrulline dipeptide derivative or combination thereof composition administered daily is between 1 g and 30 g. Most typically, the amount of citrulline dipeptide or citrulline dipeptide derivative or combination thereof composition administered daily is 8 g.

[0078] The effective amount of citrulline dipeptide or citrulline dipeptide derivative in the composition containing citrulline dipeptide administered once or more times per day is 0.001% to 50.0% by weight or between 0.001 to 90.0% (w / w). One or more doses can be administered once per day over any time period. For example, an effective dose can be administered daily for one day, several days, many days, or indefinitely on a daily basis, with citrulline dipeptide administered for 7 days and above in a cycle, depending on the desired effect. More typically, the amount of citrulline dipeptide or citrulline dipeptide derivative administered daily is 0.005%, 0.01%, 0.05%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 7%, 9%, 10%, 12%, 15%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90% (w / w). The amount of citrulline dipeptide or citrulline dipeptide derivative administered once or more times per day can be 0.1 μM to 1 M (e.g., 0.1 μM to 500 μM, 1 μM to 500 μM, 1 μM to 5 mM, 1 μM to 100 mM, 1 μM to 500 mM, 5 μM to 500 μM, 5 μM to 5 mM, 5 μM to 100 mM, 5 μM to 500 mM, 50 μM to 500 μM, 50 μM to 5 mM). One dose or multiple doses can be administered over any time period of the day. For example, an effective dose can be given daily for one day, several days, many days, or indefinitely on a daily basis.

[0079] The amount of the composition containing citrulline dipeptide or salt, ester, derivative thereof can be selected as needed.

[0080] Various forms and formulations of the composition containing citrulline dipeptide are contemplated. The composition will be formulated as a nutritional or dietary supplement, a (medical) food, an animal feed, in liquid or solid form, comprising the citrulline dipeptide, and can also optionally include a nutritionally or pharmaceutically acceptable carrier. For internal administration, the composition of the present application can be in any appropriate form, including a solution, tablet, gel capsule, capsule, or alternative nutritional food or nutritional supplement.

[0081] The technical features, implementation methods, and beneficial effects of the present application will be further described in detail below in conjunction with specific implementation cases. The materials and reagents described in the following examples are commercially available unless otherwise specified. Example 1

[0082] The dipeptide compositions of Examples 1-1 to 1-23 were each prepared by thoroughly mixing arginine dipeptide (Di-Arg) with citrulline dipeptide (Di-Cit) using a three-dimensional double-cone mixer, as follows:

[0083] Example 2

[0084] The dipeptide compositions of Examples 2-1 to 2-16 were each prepared by thoroughly mixing citrulline dipeptide (Di-Cit) with arginine dipeptide (Di-Arg) using a three-dimensional double-cone mixer, as follows:

[0085] Example 3

[0086] The dipeptide compositions of Examples 3-1 to 3-23 were each prepared by thoroughly mixing arginine dipeptide (Di-Arg) with citrulline dipeptide (Di-Cit) using a three-dimensional double-cone mixer, as follows: Example 4

[0087] The dipeptide compositions of Examples 4-1 to 4-23 were each prepared by thoroughly mixing arginine dipeptide (Di-Arg) with citrulline dipeptide (Di-Cit) using a three-dimensional double-cone mixer, as follows: Example 5

[0088] Forty-eight male Kunming mice were randomly divided into Group A (control, no exercise), Group B (control, exercise), Group C (high-dose citrulline, Cit-H, 945 mg / kg), Group D (medium-dose citrulline dipeptide, Di-Cit-M, 472 mg / kg), Group E (low-dose citrulline dipeptide, Di-Cit-L, 236 mg / kg), and Group F (Di-Cit + Di-Arg, Di-Cit at a dose of 236 mg / kg and Di-Arg at a dose of 236 mg / kg), with 8 mice in each group. Continuous gavage was performed for 28 days, and body weight was recorded every week. The animals in Groups B, C, D, E, and F were subjected to a tail-loaded swimming endurance test after 30 minutes of administration on day 28, a treadmill endurance test on day 30, and a 90-minute unloaded swimming test after 30 minutes of administration on day 35, and blood and tissue samples were collected immediately after the swimming test.

[0089] Blood was collected via the retro-orbital route immediately after the 90-minute unloaded swimming test on day 35, and the blood was allowed to stand at room temperature for 4 hours before being centrifuged at 1500xg at 4°C for 10 min. All serum was transferred to a low-temperature tube and stored at -80°C. Liver fragments and muscle tissue were excised from the same parts and weighed.

[0090] Swimming endurance test: The loaded swimming endurance test was performed on the 28th day of administration in each group. Immediately after administration for 30 minutes, a lead wire was wrapped around the tail, with the lead wire weighing 5% of the body weight. The time from the animal entering the water to the head being completely submerged and unable to float out of the water for 10 seconds was recorded using a stopwatch. The swimming duration of each mouse was recorded.

[0091] Treadmill endurance test: Muscle endurance test was performed on day 30 of each group administration. Muscle endurance was done on an electric treadmill with a speed range of 0 to 50 cm / s, with a 10-degree incline. Uphill running involves concentric muscle contractions, which increase the work of the muscles compared to running on flat ground, resulting in faster fatigue, with the speed starting at approximately 15 cm / s, increasing by 5 cm / s every 2 minutes until reaching a speed of 50 cm / s. Animals were subjected to the treadmill test until exhaustion. The point of exhaustion was defined at the point in time at which the animal fell into the shock zone. The distance run (cm) was measured as a marker of performance.

[0092] Clinical biochemical profile: Serum was collected after 90 minutes of un-weighted swimming after 35 days of administration for analysis of clinical biochemical markers, including lactate, urea nitrogen. Part of the liver and muscle were also taken for determination of liver glycogen and muscle glycogen content.

[0093] Muscle fiber number: Muscle tissue was collected, and during the staining process of muscle sections, the muscle sample was first fixed in a paraformaldehyde solution. After dehydration treatment with xylene and alcohol, the sample was embedded in paraffin. The embedded tissue block was cut into 6-micron-thick sections. After deparaffinization of the sections, they were rehydrated with xylene and different concentrations of alcohol, then stained with hematoxylin solution for 5 minutes, and then washed with water until the color no longer faded. Then the sections were differentiated and immersed in water until the sections turned blue. Finally, the sections were stained with eosin solution for 1 minute and mounted with transparent resin to fix the dehydrated tissue sections. The number of muscle fibers was measured by ImageJ software.

[0094] Figure 1 is a graph of the body weight changes of six groups of mice during the 28-day feeding intervention. The results show that the mice in group A (control, no exercise) had a stable normal growth in body weight during the experiment; the mice in group B (control, exercise) also had a stable growth in body weight during the experiment, but the growth rate was slightly lower than that of the mice without exercise due to increased exercise; groups C (Cit-H), D (Di-Cit-M), E (Di-Cit-L), and F (Di-Cit+Di-Arg) also had a stable growth in body weight during the administration period, similar to the growth state of mice in group B.

[0095] Figure 2 is a bar graph of the weight-loaded swimming endurance of five groups of mice after 28 days of feeding intervention. The results show that the C group (Cit-H) mice had a 58% increase in weight-loaded swimming time to exhaustion after 28 days of intervention with 945 mg / kg citrulline; the D group (Di-Cit-M) mice had a 103% increase in weight-loaded swimming time to exhaustion after 28 days of intervention with 472 mg / kg citrulline dipeptide; the E group (Di-Cit-L) mice had a 52% increase in weight-loaded swimming time to exhaustion after 28 days of intervention with 236 mg / kg citrulline dipeptide; and the F group (Di-Cit+Di-Arg) mice had a 136.2% increase in weight-loaded swimming time to exhaustion after 28 days of intervention with 236 mg / kg Di-Cit and 236 mg / kg Di-Arg.

[0096] Figure 3 is a bar graph of the treadmill endurance of five groups of mice after 30 days of feeding intervention. The results show that the C group (Cit-H) mice had a 9% increase in treadmill time to exhaustion after 28 days of intervention with 945 mg / kg citrulline; the D group (Di-Cit-M) mice had a significant increase in treadmill time to exhaustion, 39% increase, after 28 days of intervention with 472 mg / kg citrulline dipeptide; the E group (Di-Cit-L) mice had a 30% increase in treadmill time to exhaustion after 28 days of intervention with 236 mg / kg citrulline dipeptide; and the F group (Di-Cit+Di-Arg) mice had a 45.4% increase in treadmill time to exhaustion after 28 days of intervention with 236 mg / kg Di-Cit and 236 mg / kg Di-Arg.

[0097] Figure 4 is a bar graph of the serum lactate content of six groups of mice after 35 days of feeding intervention. The results show that the B group (control, exercise) mice had a significant accumulation of lactate in the serum compared to the A group (control, no exercise) mice, indicating that long-term exercise caused a large accumulation of lactate in the serum; the C group (Cit-H) mice did not have an improvement in lactate accumulation after continuous intervention with citrulline; however, in the D group (Di-Cit-M), there was a significant decrease in blood lactate content after intervention with 472 mg / kg citrulline dipeptide, which was 14% lower than the B group (control, exercise); the E group (Di-Cit-L) mice had a 17% decrease in blood lactate content after intervention with 236 mg / kg citrulline dipeptide compared to the B group (control, exercise). In addition, the F group (Di-Cit+Di-Arg) mice had a 20.9% decrease in blood lactate content after 28 days of intervention with 236 mg / kg Di-Cit and 236 mg / kg Di-Arg.

[0098] Figure 5 is a bar graph of muscle glycogen content of six groups of mice after 35 days of feeding intervention. The results show that the B (control, exercise) group of mice compared to the A (control, no exercise) group of mice indicates that long term exercise causes a decrease in muscle glycogen content; the C (Cit-H) group of mice has a 28% increase in muscle glycogen content after continuous intervention with 945 mg / kg citrulline compared to the B (control, exercise) group; in the D (Di-Cit-M) group, the mice have a 31% increase in muscle glycogen content compared to the B (control, exercise) group; in the F (Di-Cit+Di-Arg) group, the mice have a 38.6% increase in muscle glycogen content compared to the B (control, exercise) group.

[0099] Figure 6 is a bar graph of serum urea nitrogen content of six groups of mice after 35 days of feeding intervention. The results show that the B (control, exercise) group of mice compared to the A (control, no exercise) group of mice indicates that long term exercise causes an increase in serum urea nitrogen content; the C (Cit-H) group of mice did not improve the serum urea nitrogen content of the mice after continuous intervention with citrulline. In the D (Di-Cit-M) group, the serum urea nitrogen content decreased by 4% after intervention with 472 mg / kg citrulline dipeptide compared to the B (control, exercise) group; in the E (Di-Cit-L) group, the serum urea nitrogen content decreased significantly by 17% after intervention with 236 mg / kg citrulline dipeptide compared to the B (control, exercise) group; in the F (Di-Cit+Di-Arg) group, the serum urea nitrogen content decreased by 26.6% after 28 days of intervention with 236 mg / kg Di-Cit and 236 mg / kg Di-Arg compared to the B (control, exercise) group.

[0100] Figure 7 is a graph of muscle fiber count results of six groups of mice after 35 days of feeding intervention. As can be seen from the results, the Di-Cit-M, Di-Cit-L, and Di-Cit+Di-Arg groups all increased the muscle fiber count of the mice, enhancing muscle function, with the Di-Cit-M group increasing by 156% and the Di-Cit+Di-Arg group increasing by 172% compared to the A (control, no exercise) group. The Di-Cit-M, Di-Cit-L, and Di-Cit+Di-Arg groups all increased the muscle fiber count of the mice, enhancing muscle function, with the Di-Cit-M group increasing by 152.6% and the Di-Cit+Di-Arg group increasing by 168.4% compared to the B (control, exercise) group. Example 6

[0101] Sixteen SD rats were randomly divided into two groups, blank and citrulline dipeptide (Di-Cit) groups, and the citrulline dipeptide group was administered Di-Cit. Single gavage, Di-Cit group dose was 476.5 mg / kg. Blood samples were collected from the tail of the rats at 0 (baseline value), 0.25, 0.5, 1, 2, and 3 h after administration. The rat serum was collected, and the NO and cGMP determinations were performed using ELISA kits.

[0102] As can be seen from the blood NO change curve of Figure 8, the peak was reached 15 minutes after taking Di-Cit, and from the AUC value of Figure 9, the promotion effect of citrulline dipeptide on NO production was more than 10% better than the blank group. As shown in Figures 10 and 11, the serum cGMP of the Di-Cit group reached a peak at 15 minutes and remained until 180 minutes. As can be seen from Figure 10, the increase effect of Di-Cit was better. In terms of AUC value, the promotion effect of Di-Cit on cGMP was 32.1% higher than the blank group. Example 7

[0103] Cell culture: HUVECs (human umbilical vein endothelial cells) were cultured in 75 cm2culture bottles, and the culture conditions were 10% fetal bovine serum (FBS), 1% penicillin-streptomycin, 1% cell supplement, and 88% endothelial cell basal medium, cultured in a cell incubator at 37°C, 5% CO2.

[0104] Treatment of HUVECs: NHEKs were seeded in 24-well plates (20,000 cells / mL), and the cells were grown to about 80%. The following groups were divided and treated with corresponding solutions for 24 hours: Group 1 (control group): culture medium; Group 2 (experimental group 1: Di-Cit): culture medium containing citrulline dipeptide, with a concentration of 0.33 mg / mL; Group 3 (experimental group 2: Di-Cit + Di-Arg): culture medium containing 1:1 citrulline dipeptide and arginine dipeptide, with a concentration of 0.165 mg / mL for citrulline dipeptide and 0.165 mg / mL for arginine dipeptide. After 24 hours, the cell supernatant was collected and incubated overnight (12 h) at 4°C.

[0105] NO content test: NO is easily oxidized in vivo or in aqueous solution to form NO2 and NO3. In acidic conditions, NO reacts with diazonium sulfonic acid amine to form diazonium compounds, and further coupled with naphthalene ethylenediamine. The product has a characteristic absorption peak at 550 nm. The content of NO was calculated by measuring the absorbance value. 2- oxidation. In acidic conditions, NO 2- forms a diazonium compound with diazonium sulfonic acid amine and is further coupled with naphthalene ethylenediamine. The product has a characteristic absorption peak at 550 nm. The content of NO was calculated by measuring the absorbance value.

[0106] Data statistics and analysis: Graphpad Prism7 statistical software was used for data graphing analysis.

[0107] Figure 12 is a graph of the results of testing the NO content of three groups of cells. As shown in Figure 12, compared with the control group, the Di-Cit and Di-Cit+Di-Arg groups can promote the generation of NO in cells. Compared with the Di-Cit group, the Di-Cit+Di-Arg group has a better effect of promoting the generation of NO, and enhances the NO signal.

[0108] In summary, the method or composition of the present application can increase the level or signal of nitric oxide, or increase the level of cyclic guanosine monophosphate, or increase the level of nitrite, can enhance or improve muscle function and / or improve exercise performance and / or prevent or relieve fatigue. Specifically, it can relieve or prevent muscle dysfunction, improve mitochondrial function in muscle, improve insulin resistance in muscle, increase muscle mass, increase the number of muscle fibers, increase muscle strength and endurance, improve skeletal muscle glucose transport and metabolism, relieve or prevent muscle injury, and reduce muscle fatigue; increase running and / or swimming distance, increase exercise time, increase running and / or swimming speed, improve exercise endurance or explosive power, reduce post-exercise inflammation and muscle fatigue, and improve muscle contraction during exercise; prevent post-exercise body fatigue and accelerate post-exercise recovery.

[0109] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Any person skilled in the art can make various changes, modifications, replacements and variations to these embodiments without departing from the principles and purposes of the present application, and the scope of the present application is defined by the claims and their equivalents.

Claims

1. A method of enhancing or improving muscle function and / or increasing athletic performance and / or preventing or alleviating fatigue and / or increasing or improving nitric oxide signaling or levels, characterized in that, The method comprises administering to the subject a citrulline dipeptide or a salt, ester, derivative thereof.

2. The method of claim 1, wherein, The enhancing or improving muscle function comprises one or more of the following: relieving or preventing muscle dysfunction, improving mitochondrial function in muscle, improving insulin resistance in muscle, increasing muscle mass, increasing the number of muscle fibers, increasing muscle strength and endurance, increasing glucose transport, metabolism in skeletal muscle, relieving or preventing muscle damage, and reducing muscle fatigue; the improving athletic performance comprises one or more of the following: increasing running and / or swimming distance, increasing exercise time, increasing running and / or swimming speed, increasing exercise endurance or explosive power, reducing post-exercise inflammation and muscle fatigue, improving muscle contraction during exercise; the preventing or relieving fatigue comprises preventing post-exercise physical fatigue, accelerating post-exercise recovery.

3. The method according to claim 1 or 2, characterized in that, The method reduces lactic acid accumulation, or maintains or increases muscle glycogen content, or maintains or reduces urea nitrogen content, and / or increases or improves nitric oxide and / or cyclic guanosine monophosphate levels.

4. The method according to claim 1 or 2, characterized in that, The method enhances or improves muscle function and / or improves athletic performance and / or prevents or relieves fatigue by increasing nitric oxide levels or signals, or increasing cyclic guanosine monophosphate levels, or increasing nitrite levels.

5. The method according to any one of claims 1 to 4, characterized in that, The method further comprises administering to the subject an arginine dipeptide or a salt, ester, derivative thereof.

6. The method of claim 5, wherein, The weight ratio of the arginine dipeptide or a salt, ester, derivative thereof to the citrulline dipeptide or a salt, ester, derivative thereof is 1:50 to 50:

1.

7. The method according to any one of claims 1 to 6, characterized in that, The muscle function or athletic performance of the subject in the administration group is increased or improved and / or fatigue is prevented or relieved by more than 10%, 30%, 40%, 50%, 60%, 70%, or 90% relative to the subject who does not receive administration, and the nitric oxide signal or level of the subject in the administration group is increased or improved by more than 10%, 30%, 40%, 50%, 60%, 70%.

8. The method according to any one of claims 1 to 7, characterized in that, The subject is a human or a mammal.

9. The method according to any one of claims 1-8, characterized in that, The citrulline dipeptide or a salt, ester, derivative thereof is prepared into a solid preparation or a liquid preparation.

10. The method according to any one of claims 1 to 9, characterized in that, The citrulline dipeptide or a salt, ester, derivative thereof is in the form of a lotion, paste, suppository, tablet, pill, granule, powder, film, capsule, beverage, aerosol, spirit, tincture, tonic, liquid suspension, sugar syrup.

11. The method according to any one of claims 1-10, characterized in that, The administration dose of the citrulline dipeptide or a salt, ester, derivative thereof is 0.1 μM to 1 M or 0.1-30 g or 0.001 to 90.0% (w / w).

12. The method according to any one of claims 1-11, characterized in that, A component for increasing nitric oxide signal or level is further comprised, and the component is coenzyme Q10, vitamin E, vitamin C, carnosine, lycopene, creatine, arginine, cysteine, resveratrol, taurine, ergothioneine, glutathione, and / or citrulline and a salt thereof.

13. Use of a citrulline dipeptide or a salt, ester, derivative thereof in the manufacture of a composition for enhancing or improving muscle function and / or improving athletic performance and / or preventing or relieving fatigue and / or increasing or improving nitric oxide signal or level.

14. Use according to claim 13, characterized in that, The enhancing or improving muscle function comprises one or more of the following: relieving or preventing muscle dysfunction, improving mitochondrial function in muscle, improving insulin resistance in muscle, increasing muscle mass, increasing the number of muscle fibers, increasing muscle strength and endurance, increasing glucose transport, metabolism in skeletal muscle, relieving or preventing muscle damage, and reducing muscle fatigue; the improving athletic performance comprises one or more of the following: increasing running and / or swimming distance, increasing exercise time, increasing running and / or swimming speed, increasing exercise endurance or explosive power, reducing post-exercise inflammation and muscle fatigue, improving muscle contraction during exercise; the preventing or relieving fatigue comprises preventing post-exercise physical fatigue, accelerating post-exercise recovery.

15. Use according to claim 13 or 14, characterized in that, The composition reduces lactic acid accumulation, or maintains or increases muscle glycogen content, or maintains or reduces urea nitrogen content, and / or increases or improves nitric oxide signaling or levels.

16. Use according to claim 13 or 14, characterized in that The composition enhances or improves muscle function and / or improves athletic performance and / or prevents or relieves fatigue by increasing nitric oxide levels or signaling, or increasing cyclic guanosine monophosphate levels, or increasing nitrite levels.

17. Use according to any one of claims 13-16, characterized in that, The composition further comprises: an arginine dipeptide or a salt, ester, derivative thereof.

18. Use according to claim 17, characterized in that The weight ratio of the arginine dipeptide or a salt, ester, derivative thereof to the citrulline dipeptide or a salt, ester, derivative thereof is 1:50 to 50:

1.

19. Use according to any one of claims 13-18, characterized in that, The muscle function or athletic performance of the subject in the administration group is increased or improved and / or fatigue is prevented or relieved by greater than 10%, 30%, 40%, 50%, 60%, 70%, or 90% relative to a subject who does not receive the administration, and the nitric oxide signaling or levels of the subject in the administration group is increased or improved by greater than 10%, 30%, 40%, 50%, 60%, 70%.

20. The use according to any one of claims 13 to 19, characterized in that, The citrulline dipeptide or a salt, ester, derivative thereof is prepared into a solid preparation or a liquid preparation.

21. The use according to any one of claims 13 to 20, characterized in that, The citrulline dipeptide or a salt, ester, derivative thereof is in the form of a lotion, paste, suppository, tablet, pill, granule, powder, film, capsule, beverage, aerosol, spirit, tincture, tonic, liquid suspension, syrup.

22. The use according to any one of claims 13 to 21, characterized in that, The administration dose of the citrulline dipeptide or a salt, ester, derivative thereof is 0.1 μM to 1 M or 0.1-30 g or 0.001 to 90.0% (w / w).

23. A composition characterized in that, The composition comprises a citrulline dipeptide or a salt, ester, derivative thereof, and a citrulline dipeptide or a salt, ester, derivative thereof.

24. The composition of claim 23, wherein, The composition is used for enhancing or improving muscle function and / or improving athletic performance and / or preventing or relieving fatigue, and / or increasing or improving nitric oxide signaling or levels in a subject.

25. The composition of claim 24, wherein, The enhancing or improving muscle function comprises one or more of the following: relieving or preventing muscle dysfunction, improving mitochondrial function in muscle, improving insulin resistance in muscle, increasing muscle mass, increasing the number of muscle fibers, increasing muscle strength and endurance, increasing skeletal muscle glucose transport, metabolism, relieving or preventing muscle damage, and reducing muscle fatigue; the improving athletic performance comprises one or more of the following: increasing running and / or swimming distance, increasing exercise time, increasing running and / or swimming speed, increasing exercise endurance or explosive power, reducing post-exercise inflammation and muscle fatigue, improving muscle contraction during exercise; the preventing or relieving fatigue comprises preventing post-exercise physical fatigue, accelerating post-exercise recovery.

26. The composition of any one of claims 23-25, wherein, The composition reduces lactic acid accumulation, or maintains or increases muscle glycogen content, or maintains or decreases blood urea nitrogen content, and / or increases or improves levels of nitrite and / or cyclic guanosine monophosphate.

27. The composition of any one of claims 23-25, wherein, The composition enhances or improves muscle function and / or improves athletic performance and / or prevents or relieves fatigue by increasing levels or signaling of nitric oxide, or increasing levels of cyclic guanosine monophosphate, or increasing levels of nitrite.

28. The composition of any one of claims 23-27, wherein, The arginine dipeptide or salt, ester, derivative thereof and the citrulline dipeptide or salt, ester, derivative thereof are in a weight ratio of 1:50 to 50:

1.

29. The composition of any one of claims 23-28, wherein, Muscle function or athletic performance of the subject administered the composition is increased or improved and / or fatigue is prevented or relieved by greater than 10%, 30%, 40%, 50%, 60%, 70%, or 90% relative to a subject not receiving the administration, and nitric oxide signaling or levels of the subject administered the composition is increased or improved by greater than 10%, 30%, 40%, 50%, 60%, 70%.

30. The composition of any one of claims 26-29, wherein, The composition is in an amount of 0.1 μM to 1 M or 0.1-30 g or 0.001 to 90.0% (w / w).

31. A method of increasing or enhancing the level of nitrous acid and / or cyclic guanosine monophosphate, characterized in that, The method comprises: administering a citrulline dipeptide or salt, ester, derivative thereof to the subject.

32. The method of claim 31, wherein, The method further comprises: administering an arginine dipeptide or salt, ester, derivative thereof to the subject.

33. The method of claim 32, wherein, The arginine dipeptide or salt, ester, derivative thereof and the citrulline dipeptide or salt, ester, derivative thereof are in a weight ratio of 1:50 to 50:

1.

34. The method of any one of claims 31-33, wherein, Levels of nitrite and / or cyclic guanosine monophosphate of the subject administered the group are increased or improved by greater than 10%, 30%, 40%, 50%, 60%, 70%, or 90% relative to a subject not receiving the administration.

35. The method of any one of claims 31-34, wherein, The subject is a human or a mammal.

36. The method of any one of claims 31-35, wherein, The citrulline dipeptide or salt, ester, derivative thereof is formulated as a nutraceutical, a dietary supplement, a food, a beverage, or an animal feed.

37. The method of any one of claims 31-36, wherein, The citrulline dipeptide or salt, ester, derivative thereof is administered in an amount of 0.1 μM to 1 M or 0.1-30 g or 0.001 to 90.0% (w / w).

38. Use of a citrulline dipeptide or salt, ester, derivative thereof in the manufacture of a composition for increasing or improving levels of nitrite and / or cyclic guanosine monophosphate.

39. The use according to claim 38, characterized in that The composition further comprises: an arginine dipeptide or salt, ester, derivative thereof.

40. The use according to claim 39, characterized in that The arginine dipeptide or salt, ester, derivative thereof and the citrulline dipeptide or salt, ester, derivative thereof are in a weight ratio of 1:50 to 50:

1.

41. The use according to any one of claims 38-40, characterized in that, wherein the citrulline dipeptide or salt, ester, derivative thereof is prepared into a solid preparation or a liquid preparation.

Images