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WO2025244469A1 - Composition pour la prévention ou le traitement de maladies musculaires comprenant un métabolite probiotique en tant que principe actif - Google Patents

Composition pour la prévention ou le traitement de maladies musculaires comprenant un métabolite probiotique en tant que principe actif

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Publication number
WO2025244469A1
WO2025244469A1 PCT/KR2025/007036 KR2025007036W WO2025244469A1 WO 2025244469 A1 WO2025244469 A1 WO 2025244469A1 KR 2025007036 W KR2025007036 W KR 2025007036W WO 2025244469 A1 WO2025244469 A1 WO 2025244469A1
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WO
WIPO (PCT)
Prior art keywords
muscle
composition
chemical formula
paragraph
compound
Prior art date
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Pending
Application number
PCT/KR2025/007036
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English (en)
Korean (ko)
Inventor
이충환
김수현
김선여
홍성민
이은유
임윤숙
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Metamass Corp
Original Assignee
Metamass Corp
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Publication date
Application filed by Metamass Corp filed Critical Metamass Corp
Publication of WO2025244469A1 publication Critical patent/WO2025244469A1/fr
Pending legal-status Critical Current
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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • the present invention relates to a composition for preventing or treating muscle disease, comprising a probiotic metabolite as an active ingredient.
  • Prebiotics, probiotics, and postbiotics are relatively new terms used to describe a variety of substances that confer health and nutritional benefits to animals.
  • the term prebiotic refers to substances that stimulate the growth or activity of bacteria in the digestive tract of animals, leading to beneficial health effects.
  • Prebiotics can be selectively fermented ingredients that induce specific changes in both the composition and activity of the gastrointestinal microflora, conferring health benefits to the host.
  • Probiotics generally refer to microorganisms that contribute to the intestinal bacterial balance and, consequently, to maintaining health.
  • Many species of lactic acid bacteria (LAB), such as Lactobacillus and Bifidobacterium are commonly considered probiotics, although some species of Bacillus and some yeasts have also been identified as suitable candidates.
  • Postbiotics refer to non-viable bacterial products or metabolic by-products derived from probiotic organisms that possess biological activity in the host.
  • probiotics to improve animal health and nutrition has been shown to be effective in a variety of diseases and health conditions.
  • prebiotics and postbiotics offer potential alternatives or adjunctive therapies to the use of live microorganisms.
  • the consumption of probiotic bacteria can potentially stabilize the immunological barrier in the gut mucosa by reducing the production of local proinflammatory cytokines.
  • alterations in the characteristics of the indigenous microbiota by probiotic therapy have been shown to reverse some immunological disturbances in human conditions such as Crohn's disease, food allergy, and atopic eczema.
  • muscle atrophy can be caused by a variety of factors, including the absence of mechanical stimulation, starvation, and cancer.
  • Muscle atrophy can be defined as the loss of muscle tissue resulting from disuse, disease of the muscle itself, or damage to the nerves that control it. In general, disuse can lead to a significant loss of muscle strength, which can gradually progress to muscle atrophy. Furthermore, individuals living in environments without gravity can also experience muscle weakness due to decreased calcium and muscle strength.
  • Muscle atrophy due to disease of the muscle itself includes myasthenia gravis, muscular dystrophy (progressive muscular dystrophy, myotonic dystrophy, Duchenne, Becker, limb-girdle, facioscapulohumeral), and inflammation that occurs in the muscle itself, and muscle atrophy due to damage to the nerves that control the muscle includes spinal muscular amyotrophy (Berardnig-Hoffmann type, Kugelberg-Welander disease), amyotrophic lateral sclerosis (ALS): Lou Gehrig's disease, and spinobular muscular atrophy (Kennedy's disease).
  • spinal muscular amyotrophy Boardnig-Hoffmann type, Kugelberg-Welander disease
  • ALS amyotrophic lateral sclerosis
  • Skennedy's disease spinobular muscular atrophy
  • Sarcopenia refers to a condition in which skeletal muscle mass and function are reduced. Sarcopenia can be caused by a variety of factors, including aging, hormonal imbalances, nutritional deficiencies, lack of physical activity, inflammation, and degenerative diseases. Aging and sex hormone deficiencies are known to be the primary causes. Advances in medical technology and the development of various treatments have led to increased life expectancy worldwide, leading to a growing aging population. Consequently, the demand for sarcopenia treatment is expected to continue to grow.
  • the inventors of the present invention isolated useful metabolites from probiotic strains and confirmed that the isolated compounds have effects of increasing muscle mass and inhibiting muscle atrophy, thereby completing the present invention.
  • the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating muscle disease, which comprises a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a food composition for preventing or improving muscle disease, which comprises a compound represented by the above chemical formula 1 or a food-wise acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a pharmaceutical composition for promoting muscle differentiation, muscle regeneration or muscle strengthening, comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a food composition for promoting muscle differentiation, muscle regeneration or muscle strengthening, which comprises a compound represented by the above chemical formula 1 or a food-wise acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a pharmaceutical composition for increasing muscle mass or promoting muscle production, comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a food composition for increasing muscle mass or promoting muscle production, which comprises a compound represented by the above chemical formula 1 or a food-wise acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a pharmaceutical composition for improving muscle function, which comprises a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a food composition for improving muscle function, which comprises a compound represented by the above chemical formula 1 or a food-wise acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a method for treating muscle disease, comprising the step of administering to a subject a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition for preventing or treating muscle disease, which comprises a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a food composition for preventing or improving muscle disease, which comprises a compound represented by the above chemical formula 1 or a food-wise acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for promoting muscle differentiation, muscle regeneration or muscle strengthening, comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a food composition for promoting muscle differentiation, muscle regeneration or muscle strengthening, which comprises a compound represented by the above chemical formula 1 or a food-wise acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for increasing muscle mass or promoting muscle production, comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a food composition for increasing muscle mass or promoting muscle production, which comprises a compound represented by the above chemical formula 1 or a food-wise acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for improving muscle function, comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a food composition for improving muscle function, which comprises a compound represented by the above chemical formula 1 or a food-wise acceptable salt thereof as an active ingredient.
  • the present invention provides a method for treating muscle disease, comprising the step of administering to a subject a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.
  • the probiotic metabolites of the present invention were confirmed to protect muscle cells and promote muscle fiber differentiation. Furthermore, in an animal model of dexamethasone-induced muscle atrophy or sarcopenia, they were confirmed to increase muscle mass and muscle function, suppress the expression of factors associated with muscle breakdown, and increase the expression of factors associated with muscle synthesis and regeneration. Furthermore, in an animal model of fasting-induced muscle atrophy or sarcopenia, they were confirmed to increase muscle function, protect against muscle tissue damage, suppress the expression of factors associated with muscle breakdown, and increase the expression of factors associated with muscle synthesis and regeneration, and thus can be usefully utilized in related industries.
  • Figure 1 is a schematic diagram of the production and experimental process of a dexamethasone-induced muscle atrophy or sarcopenia animal model.
  • Figure 2 is a schematic diagram illustrating the production and experimental process of a fasting-induced muscle atrophy or sarcopenia animal model.
  • Figure 3 is a diagram confirming the MGO-AGEs crushing ability according to the treatment of the probiotic metabolite of the present invention.
  • Figure 4 is a diagram confirming the cell viability and cell proliferation ability of muscle cells according to the probiotic metabolite of the present invention and dexamethasone treatment.
  • Figure 5 is a diagram showing the formation of myotubes confirmed by Jenner-Giemsa staining according to the probiotic metabolite of the present invention and dexamethasone treatment (A: staining result, B: quantification of myotube diameter).
  • Figure 6 is a diagram showing the expression of muscle breakdown proteins analyzed by Western blot according to the probiotic metabolites of the present invention and dexamethasone treatment (A: Western blot analysis, B: quantification of analysis results).
  • Figure 7 is a diagram showing the expression of muscle production and growth proteins according to the probiotic metabolites of the present invention and dexamethasone treatment, analyzed by Western blot (A: Western blot analysis, B: quantification of analysis results).
  • Figure 8 is a diagram showing the quantification of body weight changes and food intake according to the administration of probiotic metabolites to an animal model of dexamethasone-induced muscle disease (A: confirmation of body weight change, B: quantification of body weight change, C: quantification of food intake).
  • Figure 9 shows the quantification of muscle mass by muscle according to the administration of probiotic metabolites to an animal model of dexamethasone-induced muscle disease.
  • Figure 10 is a diagram showing muscle function confirmed according to the administration of probiotic metabolites to an animal model of dexamethasone-induced muscle disease (A: running time quantification, B: speed quantification, C: grip strength quantification).
  • Figure 11 is a diagram showing the results of micro-CT analysis of calf thickness according to administration of probiotic metabolites to an animal model of dexamethasone-induced muscle disease (A: micro-CT results, B: calf area quantification, C: fibula and tibia distance quantification).
  • Figure 12 is a Western blot analysis of the expression of muscle degradation proteins in tissues following administration of probiotic metabolites to an animal model of dexamethasone-induced muscle disease (A: Western blot analysis, B: quantification of analysis results).
  • Figure 13 is a diagram showing the expression of Atrogin-1 in tissues analyzed by immunohistochemical staining according to the administration of probiotic metabolites to an animal model of dexamethasone-induced muscle disease (A: staining results, B: quantification of staining results).
  • Figure 14 is a Western blot analysis of the expression of fibrotic factors in tissues following administration of probiotic metabolites to an animal model of dexamethasone-induced muscle disease (A: Western blot analysis, B: quantification of analysis results).
  • Figure 15 is a diagram showing the collagen accumulation confirmed by Sirius red staining following administration of probiotic metabolites to an animal model of dexamethasone-induced muscle disease (A: staining result, B: quantification of staining result).
  • Figure 16 is a Western blot analysis of the expression of myogenic factors according to the administration of probiotic metabolites to an animal model of dexamethasone-induced muscle disease (A: Western blot analysis, B: quantification of analysis results).
  • Figure 17 is a diagram showing the expression of MyH confirmed by immunohistochemical staining according to the administration of probiotic metabolites to an animal model of dexamethasone-induced muscle disease (A: staining result, B: quantification of staining result).
  • Figure 18 is a diagram showing the muscle fiber size confirmed by H&E staining according to the administration of probiotic metabolites to an animal model of dexamethasone-induced muscle disease (A: staining result, B: quantification of staining result).
  • Figure 19 is a Western blot analysis of the activation of the muscle synthesis pathway following administration of probiotic metabolites to an animal model of dexamethasone-induced muscle disease (A: Western blot analysis, B: quantification of analysis results).
  • Figure 20 is a diagram showing the results of multivariate statistical analysis of the metabolic differences between groups in blood and gastrocnemius muscle tissue according to the administration of probiotic metabolites in a dexamethasone-induced muscle atrophy or sarcopenia animal model.
  • Figure 21 is a diagram analyzing the pattern of metabolite content and changed metabolic pathways between groups in blood and gastrocnemius muscle tissue according to the administration of probiotic metabolites in an animal model of dexamethasone-induced muscular atrophy or sarcopenia (A. Comparison of metabolite content between groups, B. Changed major metabolic pathways).
  • Figure 22 is a diagram confirming the effect of improving muscle strength by administering probiotic metabolites to a fasting-induced muscle disease animal model.
  • Figure 23 is a diagram showing the muscle fiber protection effect confirmed by administration of probiotic metabolites to a fasting-induced muscle disease animal model using H&E staining.
  • Figure 24 is a diagram showing the activity of creatine kinase, an indicator of muscle damage in the blood, following administration of probiotic metabolites to a fasting-induced muscle disease animal model.
  • Figure 25 is a diagram showing the concentration of ⁇ -hydroxybutanoic acid, an indicator of muscle damage in the blood, following administration of probiotic metabolites to a fasting-induced muscle disease animal model.
  • Figure 26 is a diagram confirming the correlation between fasting and body composition.
  • Figure 27 is a Western blot analysis of the expression of muscle protein degradation factors following administration of probiotic metabolites to a fasting-induced muscle disease animal model (A: Western blot analysis, B: quantification of analysis results).
  • Figure 28 is a Western blot analysis of protein expression of the muscle degradation pathway following administration of probiotic metabolites to a fasting-induced muscle disease animal model (A: Western blot analysis, B: quantification of analysis results).
  • Figure 29 is a Western blot analysis of protein expression of muscle synthesis and growth pathways following administration of probiotic metabolites to a fasting-induced muscle disease animal model (A: Western blot analysis, B: quantification of analysis results).
  • Figure 30 is a Western blot analysis of the expression of cell death factors following administration of probiotic metabolites to a fasting-induced muscle disease animal model (A: Western blot analysis, B: quantification of analysis results).
  • Figure 31 is a Western blot analysis of the expression of inflammatory and oxidative stress factors following administration of probiotic metabolites to a fasting-induced muscle disease animal model.
  • the present invention provides a pharmaceutical composition for preventing or treating muscle disease, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound of the above chemical formula 1 of the present invention may be named 2-hydroxyisovaleric acid and may be a compound with CAS number 17407-56-6.
  • prevention means any act of suppressing symptoms or delaying progression of a specific disease by administering the composition of the present invention.
  • treatment means any act of improving or beneficially altering the symptoms of a specific disease by administering the composition of the present invention.
  • pharmaceutically acceptable salts means those salts which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, and the like, and which are proportional to a reasonable advantage/disadvantage ratio.
  • S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or formed using other methods used in the art, such as ion exchange.
  • inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids
  • organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or formed using other methods used in the art, such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium, and N + ( C1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.
  • the pharmaceutical composition of the present invention may further include an adjuvant in addition to the active ingredient.
  • an adjuvant known in the art may be used without limitation. However, for example, Freund's complete adjuvant or incomplete adjuvant may be further included to enhance its effectiveness.
  • the pharmaceutical composition according to the present invention can be prepared in a form in which the active ingredient is mixed with a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier includes carriers, excipients, and diluents commonly used in the pharmaceutical field.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • the pharmaceutical composition of the present invention can be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injection solutions, each according to a conventional method.
  • Solid preparations for oral administration include tablets, pills, powders, granules, and capsules, and such solid preparations can be prepared by mixing the active ingredient with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, and gelatin.
  • excipients such as starch, calcium carbonate, sucrose, lactose, and gelatin.
  • lubricants such as magnesium stearate and talc can also be used.
  • Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups, and in addition to commonly used diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives can be included.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories.
  • Non-aqueous solvents and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • Suppository bases include witepsol, Tween 61, cocoa butter, laurin, and glycerogelatin.
  • composition according to the present invention can be administered to a subject via various routes. All modes of administration are contemplated, including oral, intravenous, intramuscular, subcutaneous, and intraperitoneal injection.
  • the dosage of the pharmaceutical composition according to the present invention is selected in consideration of the age, weight, sex, physical condition, etc. of the subject. It is obvious that the concentration of the active ingredient included in the pharmaceutical composition can be selected in various ways depending on the subject, and it is preferably included in the pharmaceutical composition at a concentration of 0.01 to 5,000 ⁇ g/ml. If the concentration is less than 0.01 ⁇ g/ml, pharmaceutical activity may not be observed, and if it exceeds 5,000 ⁇ g/ml, it may be toxic to the human body.
  • the compound may increase muscle mass, and the increase in muscle mass may be an increase in muscle canal diameter or muscle thickness.
  • the compound may increase muscle function.
  • the compound may suppress the expression of a muscle degradation factor
  • the muscle degradation factor may be a protein selected from the group consisting of muscle atrophy F-box (MAFbx/Atrogin-1), muscle-specific RING finger protein 1 (MuRF1), forkhead box O3 (FoxO3a), and glucocorticoid receptor (GR).
  • the compound may increase the expression of a muscle growth factor
  • the muscle growth factor may be myoblast determination protein 1 (MyoD), myogenin, or myosin heavy chain (MyH).
  • the compound may increase phosphorylation or expression of a muscle synthesis pathway protein
  • the muscle synthesis pathway protein may be a protein selected from the group consisting of mammalian target of rapamycin (mTOR), AKT Serine/Threonine Kinase 1 (AKT), insulin like growth factor 1 receptor (IGF-1R), and NAD-dependent deacetylase sirtuin 2 (SIRT2).
  • the compound may inhibit phosphorylation of a muscle degradation pathway, and the muscle degradation pathway may be an extracellular signal-mediated kinase (ERK1/2).
  • ERK1/2 extracellular signal-mediated kinase
  • the compound may reduce the LC3(1A/1B-light chain 3)B-II/LC3B-I ratio of the muscle degradation pathway.
  • the compound may inhibit fibrosis of muscle tissue, and the inhibition of fibrosis may be by inhibiting Mothers against decapentaplegic homolog 7 (Smad7) in muscle tissue, and may be by inhibiting collagen accumulation in muscle tissue.
  • Smad7 decapentaplegic homolog 7
  • the compound may reduce a muscle damage indicator in the blood, and the muscle damage indicator may be creatine kinase or ⁇ -hydroxybutyrate.
  • the compound may regulate the expression of a metabolite related to muscle synthesis.
  • regulating the expression of the muscle synthesis-related metabolite may be by increasing the amount of a metabolite selected from the group consisting of glycine, tyrosine, sucrose, pyruvate, thymine, ethylene glycol, and 1,2-propanediol in serum, and by increasing the amount of 12-S-HETE or LPE 18:3 in muscle.
  • a metabolite selected from the group consisting of glycine, tyrosine, sucrose, pyruvate, thymine, ethylene glycol, and 1,2-propanediol in serum
  • regulating the expression of the muscle synthesis-related metabolites may be by reducing the amount of lactose, mannitol, sorbitol, 2-hydroxybutyric acid, fumaric acid, and uric acid in serum, and by reducing the amount of glycine or mannitol in muscle.
  • the muscle disease may be a disease selected from the group consisting of muscular atrophy, myopathy, muscular degeneration, myasthenia, muscular injury, dystrophinopathy, myopathy, muscular dystrophy, cachexia, and sarcopenia, and is preferably muscular atrophy or sarcopenia, but is not limited thereto.
  • the present invention provides a food composition for preventing or improving muscle disease, which comprises a compound represented by the above chemical formula 1 or a food-wise acceptable salt thereof as an active ingredient.
  • improvement means any action that at least reduces a parameter associated with the condition being treated, for example, the severity of a symptom.
  • the food composition of the present invention may contain, in addition to containing the effective ingredient of the present invention, various flavoring agents or natural carbohydrates as additional ingredients, like conventional food compositions.
  • natural carbohydrates examples include monosaccharides such as glucose, fructose, etc.; disaccharides such as maltose, sucrose, etc.; and polysaccharides such as dextrin, cyclodextrin, etc., and common sugars, and sugar alcohols such as xylitol, sorbitol, erythritol, etc.
  • natural flavoring agent thaumatin
  • stevia extract e.g., rebaudioside A, glycyrrhizin, etc.
  • synthetic flavoring agent sacharin, aspartame, etc.
  • the food composition of the present invention can be formulated in the same manner as the pharmaceutical composition and used as a functional food or added to various foods.
  • Foods to which the composition of the present invention can be added include, for example, beverages, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gum, candy, ice cream, alcoholic beverages, vitamin complexes, and health supplements.
  • the food composition may contain, in addition to the extract as an active ingredient, various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.
  • the food composition of the present invention may contain fruit pulp for producing natural fruit juice, fruit juice drinks, and vegetable drinks.
  • the functional food composition of the present invention can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of preventing or treating muscle diseases.
  • the term "health functional food composition" in the present invention refers to a food manufactured and processed using raw materials or ingredients having functionality useful to the human body according to Act No. 6727 on Health Functional Foods, and means to be consumed for the purpose of obtaining a useful effect for health purposes such as regulating nutrients for the structure and function of the human body or physiological effects.
  • the health functional food of the present invention may include conventional food additives, and whether it is suitable as a food additive is determined by the specifications and standards for the relevant item according to the general provisions and general test methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety, unless otherwise specified.
  • Items listed in the "Food Additives Codex” include, for example, chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; Examples thereof include natural additives such as persimmon pigment, licorice extract, crystalline cellulose, high-molecular weight pigment, and guar gum; mixed preparations such as sodium L-glutamate preparations, noodle additive alkaline agents, preservative preparations, and tar color preparations.
  • a health functional food in tablet form can be prepared by mixing the active ingredient of the present invention with excipients, binders, disintegrants, and other additives, granulating the mixture using a conventional method, and then adding a lubricant, etc.
  • the health functional food in tablet form can contain a maturing agent, etc., if necessary.
  • hard capsules can be prepared by filling a mixture of the active ingredient of the present invention with additives such as excipients into a conventional hard capsule
  • soft capsules can be prepared by filling a mixture of the active ingredient of the present invention with additives such as excipients into a capsule base such as gelatin.
  • the above soft capsules may contain plasticizers such as glycerin or sorbitol, coloring agents, preservatives, etc., as needed.
  • the ring-shaped health functional food can be prepared by molding a mixture of the active ingredient of the present invention with an excipient, a binder, a disintegrant, etc., using a conventionally known method, and, if necessary, can be coated with white sugar or another coating agent, or the surface can be coated with a material such as starch or talc.
  • the granular health functional food can be manufactured into a granular form by mixing a mixture of the active ingredient of the present invention with an excipient, a binder, a disintegrant, etc., using a conventionally known method, and, if necessary, can contain a flavoring agent, a flavoring agent, etc.
  • the present invention provides a pharmaceutical composition for promoting muscle differentiation, muscle regeneration or muscle strengthening, comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a food composition for promoting muscle differentiation, muscle regeneration or muscle strengthening, which comprises a compound represented by the above chemical formula 1 or a food-wise acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for increasing muscle mass or promoting muscle production, comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a food composition for increasing muscle mass or promoting muscle production, which comprises a compound represented by the above chemical formula 1 or a food-wise acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for improving muscle function, comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a food composition for improving muscle function, which comprises a compound represented by the above chemical formula 1 or a food-wise acceptable salt thereof as an active ingredient.
  • the present invention provides a method for treating muscle disease, comprising the step of administering to a subject a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.
  • the treatment method of the present invention comprises administering to a subject a therapeutically effective amount of the compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof. It is preferred that the specific therapeutically effective amount for a specific subject be applied differently depending on various factors including the type and degree of the response to be achieved, the specific composition including whether other agents are used in some cases, the age, body weight, general health condition, sex and diet of the subject, the time of administration, the route of administration and the secretion rate of the composition, the treatment period, drugs used together or simultaneously with the specific composition, and similar factors well known in the medical field.
  • the daily dosage is 0.0001 to 100 mg/kg, preferably 0.01 to 100 mg/kg, based on the amount of the pharmaceutical composition of the present invention, and can be administered 1 to 6 times a day.
  • the dosage or administration of each active ingredient should be such that the content of each active ingredient is not excessively high and side effects are not caused. Therefore, it is preferred that the effective amount of a composition suitable for the purpose of the present invention be determined in consideration of the aforementioned matters.
  • the above object is applicable to any mammal, which includes not only humans and primates, but also livestock such as cows, pigs, sheep, horses, dogs and cats.
  • the compound of chemical formula 1 of the present invention can be administered to mammals such as rats, mice, livestock, and humans via various routes. All modes of administration are conceivable, and for example, it can be administered orally, rectally, or by intravenous, intramuscular, subcutaneous, intrauterine, or intracerebroventricular injection.
  • ProM probiotic metabolite
  • Example 1 Preparation for confirmation of improvement in dexamethasone-induced muscle disease by probiotic metabolites.
  • dexamethasone (DEX)-induced muscle disease reagents were prepared.
  • oxymetholone (OXY; Sigma-Aldrich, USA) was used as a positive control.
  • curcumin (CU; Sigma-Aldrich, USA) was used as a positive control, and the probiotic metabolite and all compounds were dissolved in distilled water and used.
  • Dexamethasone (DEX; Sigma-Aldrich, USA) was used as a negative control that reduces muscle mass, inducing muscle atrophy and sarcopenia. In animal experiments, it was dissolved in 4% DMSO, 1% tween-20, and 95% saline, and in cell experiments, it was dissolved in 10% DMSO.
  • MGO-AGEs methylglyoxal-derived advanced glycation endproducts
  • TBSA 2,4,6-trinitrobenzene sulfonic acid
  • MGO-AGEs prepared by reacting methylglyoxal (MGO) with bovine serum albumin (BSA) at 37°C for 7 days, were mixed with the compound of formula 1 (100, 200, or 400 ⁇ M) and dexamethasone (100, 200, or 400 ⁇ M) at a concentration of 1 mg/mL, homogenized, and reacted for 24 hours. Then, 0.1% TNBSA and 4% NaHCO 3 were added, and reacted for 2 hours. The reaction was then terminated by adding 10% SDS and 1 N HCl, and the AGE degradation products were quantified by measuring the absorbance at 340 nm using a microplate reader (Molecular Devices, San Jose, CA, USA).
  • C2C12 cells (ATCC, USA), a mouse myoblast cell line, were cultured in Dulbecco's Modified Eagle Medium (DMEM, Welgene, Korea) supplemented with 10% fetal bovine serum (Welgene) and 1% penicillin/streptomycin at 5% CO2 and 37°C.
  • DMEM Dulbecco's Modified Eagle Medium
  • Welgene fetal bovine serum
  • penicillin/streptomycin 5% CO2 and 37°C.
  • To induce myotube differentiation of myoblasts cells were seeded at a cell density of 2.5 ⁇ 105 in 6-well plates and cultured for 2 days. When the cells reached 90% confluence, the medium was replaced with differentiation DMEM containing 2% horse serum, and the cells were treated with the compound of formula 1 or 1 ⁇ M curcumin (CU), a positive control, for 6 days during the differentiation process.
  • CU ⁇ M curcumin
  • C2C12 cells were seeded at a concentration of 1 ⁇ 10 4 cells in a 96-well plate and cultured under 5% CO 2 and 37°C conditions. When the cells were more than 80% confluent, the cells were treated with the compound of formula 1 and cultured in serum-free medium for an additional 24 hours. After that, 100 ⁇ l of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution (0.5 mg/ml, Sigma-Aldrich) was added and reacted for 2 hours. The resulting formazan product was dissolved in DMSO and the absorbance was measured at 540 nm using a microplate reader (BioTek, Winooski, VT, USA).
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
  • the length, width, and area of the root canals were measured by staining differentiated C2C12 cells with Jenner-Giemsa. After Jenner-Giemsa staining, the root canals were washed twice with cold PBS and fixed with 4% paraformaldehyde. The root canal images were then examined using an optical microscope (Olympus, Tokyo, Japan). The root canal diameters were measured from the images of each group, and the average values were quantified using Image J software.
  • mice Seven-week-old C57BL/6N mice were purchased from Orient Bio (Republic of Korea) and acclimated for 1 week before use in the experiment. Mice were housed at 23 ⁇ 1°C with a 12-h light/dark cycle and were provided unlimited access to water and a standard laboratory diet. All animal experiments were performed in accordance with the ethical guidelines established by the Laboratory Animal Research Center, College of Pharmacy, Gachon University, Seongnam, Republic of Korea, and the experimental protocol was approved by the Institutional Animal Care and Use Committee of Gachon University (GU1-2023-IA0032-00).
  • the habituated mice were divided into the following groups: a vehicle group (CON group) administered with a solvent; a DEX group administered with dexamethasone; a positive control group (OXY) treated with 50 mg/kg of oxymetholone and dexamethasone; a group treated with 5 mg/kg of the compound of formula 1 and dexamethasone (ProM 5); and a group treated with 20 mg/kg of the compound of formula 1 and dexamethasone (ProM 20).
  • the compound of formula 1 and oxymetholone were administered orally daily for 14 days, and dexamethasone was injected subcutaneously daily at a concentration of 20 mg/kg to induce muscle atrophy.
  • the specific drug administration schedule and classification of the experimental groups are shown in Fig. 1.
  • mice were humanely sacrificed, and the quadriceps femoris (QD), gastrocnemius (GCM), plantaris (PLA), extensor digitorum longus (EDL), and soleus (SOL) muscles were isolated and weighed. Muscle tissues were then frozen in liquid nitrogen and stored and fixed at -80°C.
  • QD quadriceps femoris
  • GCM gastrocnemius
  • PLA plantaris
  • EDL extensor digitorum longus
  • SOL soleus Muscle tissues were then frozen in liquid nitrogen and stored and fixed at -80°C.
  • treadmill and grip strength tests were performed. Specifically, the treadmill test was performed on days 7 and 14 after sample administration using an 8-lane treadmill with a motivation grid (JD-A-22, Republic of Korea). The treadmill test involved placing mice on a flat treadmill at a speed of 10 m/min for 3 min, increasing the speed to 2 m/min every 2 min. The running time (seconds) and speed (meters per minute) until exhaustion (maximal exercise) were recorded and compared between each group.
  • Grip strength of mice was measured using a grip dynamometer (BIO-G53, BIOSEB, USA). The grip strength test involved allowing mice to grasp a wire mesh with their forelimbs, and the grip strength value obtained when force was applied momentarily to the tail was recorded. Grip strength was measured twice, on days 7 and 14 after inducing muscle atrophy and after sample administration. Each group of mice was tested three times. The recorded grip strength values were finally quantified by dividing the value by body weight (g/g).
  • the thighs obtained from sacrificed mice were fixed in 10% neutral buffered formalin and photographed using a Micro-CT scanner (SkyScan1276, Bruker, Belgium) to measure the width and radius of the thigh.
  • the analysis conditions are as shown in Table 1 below.
  • the width and radius of the thigh were measured at the midpoint, with the total length being from the thigh head to the beginning of the fibula bone based on the tibia bone.
  • the width measurement refers to the measurement of the muscle width in the cut plane
  • the radius measurement refers to the length of the line segment from the location corresponding to the shank to the center of the fibula bone.
  • the Micro CT Scan conditions are shown in Table 1 below.
  • MicroCT scan conditions Resolution 2 K Source Voltage 40 kV Source Current 200 ⁇ A Image Pixels 18 ⁇ m Exposure Times 650 ms Rotation Step 2 ° Rotation in Degree 180 ° Average Frames 2 Filter 1 mm Al Scan Duration 3 m : 28 s
  • Quadriceps femoris (QD) and gastrocnemius (GCM) muscles obtained from sacrificed mice were fixed in 10% neutral buffered formalin, embedded in paraffin, and sectioned at 2.5 ⁇ m.
  • the cross-sectional area of each muscle tissue was measured using hematoxylin and eosin staining (H&E staining; Sigma-Aldrich, USA).
  • the degree of collagen fibrosis was analyzed using Picro-Sirius Red (Sigma-Aldrich, USA) staining. Both staining processes included deparaffinization, rehydration, dehydration, dexylene, and mounting using DPX mounting agent (Sigma-Aldrich, USA).
  • QD tissue (30 mg) or C2C12 myotubes were homogenized using RIPA buffer containing a protease/phosphatase inhibitor cocktail. The homogenate was then centrifuged at 12,000 rpm for 1 h at 4°C, and protein (30 ⁇ g) was separated by SDS-PAGE to determine expression.
  • the separated proteins were then transferred to a nitrocellulose membrane and reacted with primary antibodies of muscle atrophy F-box (MAFbx/Atrogin-1), Muscle-specific RING finger protein 1 (MuRF1), Glucocorticoid Receptor (GR), Myoblast Determination protein 1 (MyoD), Myogenin, Myosin heavy chain (MyH), The mammalian target of rapamycin (mTOR), p-mTOR, FoxO3a (Forkhead box O3), p-FoxO3a, AKT Serine/Threonine Kinase 1 (AKT), p-AKT, Mothers against decapentaplegic homolog 7 (Smad7), insulin-like growth factor 1 receptor (IGF-1R), p-IGF-1R, and NAD-dependent deacetylase sirtuin2 (SIRT2) and GAPDH, which are proteins related to muscle atrophy, at 4°C for 18 hours.
  • the membrane was washed with TBST, and HRP-conjugated secondary antibody was added and reacted at room temperature for 1 hour. After the reaction was completed, the membrane was visualized and analyzed using the ChemiDoc XRS+ imaging system (Bio-Rad, USA).
  • QD tissues sectioned at 4 ⁇ m were deparaffinized with xylene, rehydrated in 70–100% ethanol, and treated with an endogenous peroxidase blocker.
  • the sections were then washed with phosphate-buffered saline (PBS) and reacted with primary antibodies, MAFbx/Atrogin-1 and MyHC, at 4°C.
  • PBS phosphate-buffered saline
  • MAFbx/Atrogin-1 and MyHC at 4°C.
  • the sections were then washed with PBS and incubated with biotinylated anti-rabbit and anti-mouse IgG antibodies for 1 h, followed by incubation with an avidin-biotin horseradish peroxidase complex.
  • the optical density of MAFbx/Atrogin-1 and MyHC immunoreactivity in the QD tissues was then analyzed using ImageJ software (National Institutes of Health, Bethesda, MD, USA).
  • Metabolomic analysis was performed on serum and QD tissue obtained from sacrificed mice.
  • 80 ⁇ L of serum was homogenized with 1 mL of 100% methanol and incubated at -20°C for 2 hours to precipitate proteins.
  • the homogenate was centrifuged at 10,000 g for 10 minutes at 4°C, and the supernatant was dried using a speed vacuum.
  • the dried extract was re-dissolved in 0.3 mL of 50% methanol and used for instrumental analysis.
  • the homogenate was centrifuged at 10,000 g for 5 minutes at 4°C, and the supernatant was transferred to a 2-mL tube, where 0.5 mL of water was added and mixed. After centrifugation of the mixture using the same method, 1 mL of the polar layer (upper part) and 0.2 mL of the non-polar layer (lower part) were obtained from the separated mixture and dried using a speed vacuum. The dried extracts of the polar and non-polar layers of the muscle were redissolved using 0.2 mL of 50% and 100% methanol, respectively, and then filtered through a 0.22 ⁇ m syringe before being used for instrumental analysis.
  • LC-MS analysis was performed on the nonpolar layer extracts of serum and muscle. 0.1 mL of the solution was placed in a container and analyzed using UHPLC-Orbitrap-MS/MS. A Phenomenes KINETEX C18 column was used as the stationary phase, and water (A) with 0.1% formic acid and acetonitrile (B) with 0.1% formic acid were used as the mobile phase to separate the substances. In addition, GC-MS analysis was performed on the polar layer extracts of serum and muscle. After redrying the re-dissolved solution, derivatization (oximation, silylation) was performed. An Rtx-5MS column was used as the stationary phase, and the substances were separated through helium and temperature control.
  • Example 2 Preparation for confirmation of improvement in fasting-induced muscle disease by probiotic dead cells and metabolites.
  • an animal model in which fasting-induced sarcopenia was induced was created. Specifically, 10-week-old male C57BL/6J mice (Laon Bio, Republic of Korea) were habituated in individual cages under conditions of 22 ⁇ 1°C, 50 ⁇ 5% humidity, and a 12-hour light/dark cycle, with free access to water and food. All experimental procedures related to the animal model were approved by the Institutional Animal Care and Use Committee of Kyung Hee University (KHSASP-23-183).
  • mice were divided into the following groups: a normal control group (FED or CON group) continuously supplied with distilled water and diet; a control group fed only distilled water and fasted for 48 hours (FAST group); a WF group administered 50 mg/kg of a wild-type probiotic strain extract; an LProM group administered 5 mg/kg of the compound of formula 1 and fasted for 48 hours; and an HProM group administered 20 mg/kg of the compound of formula 1 and fasted for 48 hours.
  • Mice, except for the FED group received a 7-day preconditioning regimen using oral gavage, followed by a 48-hour fasting period designed to induce muscle atrophy.
  • mice in each group were fed food until 5 hours before the start of the dark condition, after which all mice were fed food, and the FED group was maintained on this condition until the end of the experiment.
  • the fasted mice were fed food for 2 hours and then food was withheld for 48 hours, and the mice in each group were provided with drinking water ad libitum.
  • the body weights of the mice were measured before the start of the fasting period and at 24 and 48 hours after the start of the fasting period.
  • the specific drug administration schedule and classification of the experimental groups are shown in Fig. 2.
  • Grip strength was evaluated using a grip strength measuring device (Grip test package GS3 (25N), Harvard Apparatus, Holliston, MA, USA) in the same manner as in Experimental Example 1-8 above, and was performed before and after fasting.
  • Grip test package GS3 25N
  • Harvard Apparatus Holliston, MA, USA
  • blood glucose and ketone levels were measured using a blood glucose and ketone meter (FreeStyle Optium, Abbott Laboratories, Australia).
  • Body composition was assessed using Dual-energy X-ray Absorptiometry (DXA; InAlyzer, Korea) after a 48-h fast. After ketamine and xylazine anesthesia, each mouse was placed on a scanner bed with its tail and limbs extended away from the body. Lean body mass and fat mass were then quantified using the manufacturer's software.
  • DXA Dual-energy X-ray Absorptiometry
  • Plasma creatine kinase activity was assayed using a colorimetric assay kit (ECPK-100, BioAssay Systems, Hayward, CA, USA) according to the manufacturer's instructions.
  • gastrocnemius muscle tissue was obtained from mice humanely sacrificed, fixed in 10% formalin, and embedded in paraffin. The tissue was then sectioned at 4 ⁇ m and stained with hematoxylin and eosin (H&E). The stained tissue was then examined under a light microscope (Nikon ECLIPSE Ci, Konan, Tokyo, Japan), and the average percentage of muscle fiber area was quantified using Image J software (National Institutes of Health, Bethesda, MD, USA).
  • Proteins were extracted from the gastrocnemius muscle tissue, and the expression of Myostatin, p-ERK1/2, extracellular signal-mediated kinase (ERK1/2), FOXO3a, MuRF-1, MAFbx/Atrogin-1, p-AMPK ⁇ , AMPK ⁇ , p-mTOR, mTOR, LC3B, Bax, Bcl-2, CuZnSOD, Nrf2, and PCNA and ⁇ -tubulin, which are proteins related to muscle atrophy, were analyzed by Western blot, in the same manner as in Experimental Example 1-11.
  • Example 1 Confirmation of improvement in dexamethasone-induced muscle atrophy by probiotic metabolites.
  • Methylglyoxal-derived advanced glycation end products are compounds produced through metabolic reactions with various biomolecules, and have recently been reported to have negative effects on skeletal muscle, reducing exercise capacity and promoting muscle atrophy. Therefore, it was confirmed whether the compound of chemical formula 1 of the present invention decomposes MGO-AGEs. As a result, as shown in Fig. 3, compared to the CON group, the DEX group did not exhibit MGO-AGE decomposition ability, but the group treated with the compound of chemical formula 1 showed excellent MGO-AGE decomposition ability in a concentration-dependent manner.
  • the compound of chemical formula 1 of the present invention increases the expression of proteins related to muscle production and growth.
  • Proteins of the MyoD and Myogenin pathways are known as proteins for muscle differentiation, and MyH is known as a marker of muscle differentiation.
  • MyoD was decreased in the group treated with DEX compared to the CON group, but it was confirmed that the decreased expression of MyoD was significantly increased when treated with the compound of chemical formula 1.
  • Myogenin showed a tendency to increase with treatment with chemical formula 1, and it was confirmed that the expression level of MyH was significantly increased with treatment with chemical formula 1.
  • the protein expression of the AKT-mTOR pathway known to promote protein synthesis and inhibit protein degradation, was confirmed.
  • the phosphorylation of mTOR and AKT was decreased in the DEX group compared to the CON group, but the phosphorylation of mTOR and AKT was significantly increased in the group treated with the compound of formula 1. Therefore, it was confirmed that the probiotic metabolite of the present invention increases muscle protein synthesis and inhibits muscle atrophy induced by DEX by activating the expression of MyoD and HyH and the mTOR-AKT pathway.
  • the compound of chemical formula 1 increased the muscle mass of the quadriceps femoris, gastrocnemius, and plantaris muscle in DEX-induced muscular dystrophy, and no significant difference was confirmed in the extensor digitorum longus and soleus muscles (FIG. 9), confirming that the compound of chemical formula 1 of the present invention has various effects on muscle protection depending on the type of muscle. Therefore, it was confirmed that the probiotic metabolite of the present invention increases muscle mass in muscles that exercise a lot, even when a muscle atrophy-inducing substance such as DEX is administered.
  • mice administered DEX muscle function was confirmed to decrease, and running speed and grip strength were confirmed to decrease.
  • running speed and grip strength were significantly increased, and in particular, it was confirmed that running speed and grip strength were significantly increased on the 14th day after the start of the experiment compared to the 7th day, confirming that the probiotic metabolite of the present invention can increase muscle function even in a state of muscle wasting.
  • the distance between the fibula and the tibia was measured, and as a result, in the group administered the compound of chemical formula 1, the distance between the fibula and the tibia was significantly increased compared to the DEX group (Fig. 11C), confirming that the lower extremity muscles were protected.
  • FoxO3a a major transcriptional regulator of muscle atrophy, was significantly increased in the DEX group compared to the CON group, but it was confirmed that the expression of FoxO3a was significantly reduced in the group treated with the compound of chemical formula 1.
  • the expression of GR was significantly increased in the DEX group compared to the CON group, but in the group administered the compound of chemical formula 1, the increased expression of GR was significantly reduced.
  • the Smad7 protein is known to be a key regulator of muscle fibrosis, and Smad7 is also known to increase muscle differentiation. As shown in Figure 14, the DEX group showed a significant decrease in Smad7 expression, but the group treated with the compound of Chemical Formula 1 showed a marked increase in the decreased expression of Smad7.
  • the quadriceps femoris tissue was stained with H&E and histologically evaluated. As a result, the size of the muscle fibers was significantly reduced in the DEX group, but in the group treated with the compound of chemical formula 1, the size of the reduced muscle fibers was confirmed to increase in a concentration-dependent manner (Fig. 18).
  • the IGF1R-AKT-mTOR and SIRT2-AKT pathways are mainly activated, and it was confirmed that the phosphorylation of IGF-1R, AKT, and mTOR decreased in the group treated with DEX compared to the CON group.
  • the group administered the compound of formula 1 it was confirmed that the decreased phosphorylation of IGF1R, AKT, and mTOR increased in a concentration-dependent manner.
  • the expression of SIRT2 was significantly decreased in the DEX group, but the compound of formula 1 increased the decreased expression of SIRT2 in a concentration-dependent manner (Fig. 19), confirming that the probiotic metabolite of the present invention improves sarcopenia induced by DEX by activating the muscle protein synthesis pathway.
  • probiotic metabolites of the present invention modulate plasma creatine kinase activity, an indicator of muscle damage.
  • plasma creatine kinase activity significantly increased in fasting-induced mice, but in the group treated with the compound of Chemical Formula 1, plasma creatine kinase activity decreased in a concentration-dependent manner, confirming a decrease in plasma metabolites associated with muscle loss.
  • the expression of myostatin protein was significantly reduced, and the expression of p-ERK1/2, a phosphorylated extracellular signal-mediated kinase, and the ratio of p-ERK1/2 and ERK1/2 were significantly reduced by treatment with the compound of chemical formula 1, confirming that the probiotic metabolite reduces the expression of muscle protein degradation factors (Fig. 27).
  • mice induced with fasting p-mTOR expression and the ratio of p-mTOR and mTOR were significantly reduced, but in the group administered the compound of formula 1, the reduced p-mTOR expression and the ratio of p-mTOR/mTOR were significantly increased, and 1A/1B-light chain 3 (LC3) protein expression and the ratio of LC3B-II/LC3B-I were increased in fasted mice, but in the group administered the compound of formula 1, LC3 protein expression and the ratio of LC3B-II/LC3B-I were significantly reduced, confirming that postbiotic metabolites inhibit muscle protein degradation (Fig. 29).
  • LC3A/1B-light chain 3 LC3 protein expression and the ratio of LC3B-II/LC3B-I were increased in fasted mice, but in the group administered the compound of formula 1, LC3 protein expression and the ratio of LC3B-II were significantly reduced, confirming that postbiotic metabolites inhibit muscle protein degradation (Fig. 29).
  • the probiotic metabolite of the present invention protects muscle cells and promotes muscle fiber differentiation.
  • the probiotic metabolite contributes to the alleviation of muscle atrophy by regulating the metabolism of sugars, amino acids, and fatty acids changed by dexamethasone.

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Abstract

La présente invention concerne un métabolite probiotique qui permet de protéger les cellules musculaires et de favoriser la différenciation des fibres musculaires. De plus, le métabolite probiotique permet d'augmenter la masse musculaire et la fonction musculaire, d'inhiber l'expression de facteurs liés à la dégradation musculaire, et d'augmenter l'expression de facteurs liés à la synthèse et à la régénération musculaires dans un modèle animal de sarcopénie ou d'atrophie musculaire induite par la dexaméthasone. De plus, le métabolite probiotique permet d'augmenter la fonction musculaire, de protéger contre les dommages causés au tissu musculaire, d'inhiber l'expression de facteurs liés à la dégradation musculaire, et d'augmenter l'expression de facteurs liés à la synthèse et à la régénération musculaires dans un modèle animal de sarcopénie ou d'atrophie musculaire induite par le jeûne.
PCT/KR2025/007036 2024-05-24 2025-05-23 Composition pour la prévention ou le traitement de maladies musculaires comprenant un métabolite probiotique en tant que principe actif Pending WO2025244469A1 (fr)

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