Methods for inhibiting muscle atrophy
Inventors
Adams, Christopher M. • Kunkel, Steven D. • Welsh, Michael
Assignees
University of Iowa Research Foundation UIRF • US Department of Veterans Affairs
Publication Number
US-10137136-B2
Publication Date
2018-11-27
Expiration Date
2032-06-06
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Abstract
In one aspect, the invention relates to methods for treating muscle atrophy by providing to an animal in need thereof an effective amount of a compound. The compound can modulate the expression levels of multiple mRNA of a muscle atrophy signature. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
Core Innovation
The invention relates to methods for treating muscle atrophy by administering to an animal an effective amount of a compound capable of modulating expression levels of multiple mRNAs of a muscle atrophy signature. The compounds include tacrine and analogs, naringenin and analogs, allantoin and analogs, conessine and analogs, tomatidine and analogs, ungerine/hippeastrine and analogs, and betulinic acid and analogs, or mixtures thereof. These compounds are useful in inhibiting muscle atrophy, promoting muscle health, promoting normal muscle function, and promoting healthy aging muscles.
Skeletal muscle atrophy is a common and debilitating condition characterized by muscle mass loss that results in weakness, increased risk of falls, fractures, respiratory infections, and loss of independence. It is caused by multiple conditions including starvation, aging, chronic diseases, neurologic diseases, immobilization, and other medical conditions. Despite advances in understanding the physiological and molecular basis of muscle atrophy, effective medical therapies to prevent or reverse it in human patients do not exist.
The invention addresses the scarcity of compounds that are potent, efficacious, and selective modulators of muscle growth and effective treatments for muscle atrophy and associated diseases. The compounds of the invention were identified using muscle atrophy mRNA expression signatures (e.g., muscle atrophy signature-1 and -2) derived from human and mouse muscle studies. Candidate compounds were selected based on their ability to down regulate multiple induced mRNAs and/or up regulate multiple repressed mRNAs of these muscle atrophy signatures, thus counteracting the gene expression changes characterizing muscle atrophy.
Claims Coverage
The patent contains multiple independent claims focused on methods for enhancing muscle formation, increasing muscle mass, or reducing muscle atrophy in animals, particularly mammals and domesticated animals, through administration of ursolic acid or its derivatives.
Method of enhancing muscle formation using ursolic acid or derivatives
A method comprising administering to an animal identified or having been identified to need enhanced muscle formation, increased muscle mass, or reduced muscle atrophy an effective amount of ursolic acid or a salt, solvate, or polymorph thereof, thereby achieving the desired muscle effect.
Animal selection and treatment conditions
Applicable to primates not diagnosed with diabetes and to various domesticated animals such as fish, crustaceans, poultry, rabbits, dogs, cats, guinea pigs, and livestock; including non-human primates, horses, pigs, sheep, goats, and cows.
Modes of administration and formulation
Administration of ursolic acid, salt, solvate, or polymorph orally, including in preservative-containing compositions such as foods, nutraceuticals, energy bars, energy drinks, supplements, capsules, cachets, or tablets.
Dosing regimens
Administering ursolic acid or derivatives in amounts from 0.1 to 250 mg/kg per day, preferably 0.5 to 100 mg/kg per day, or in absolute doses greater than 50 mg per day.
Treatment of animals without diabetes or cancer
Methods applying the ursolic acid or its derivatives to animals not diagnosed with diabetes or cancer for enhancing muscle formation, increasing muscle mass, or reducing muscle atrophy, including oral administration in specified dose ranges.
Use for aesthetic or self-improvement in humans
Administering ursolic acid or derivatives to humans identified to need muscle enhancement or atrophy reduction for aesthetic or self-improvement purposes, formulated as nutraceuticals, energy bars, drinks, or supplements, excluding those with diabetes or cancer.
The claims encompass methods of treating or enhancing muscle formation or preventing muscle atrophy in various animals by administering ursolic acid or its derivatives under defined dosages and formulations, emphasizing its use in both veterinary and human contexts including aesthetic applications.
Stated Advantages
The disclosed compounds inhibit muscle atrophy and promote muscle health, normal muscle function, and healthy aging muscles.
Compounds such as ursolic acid enhance skeletal muscle IGF-I expression and IGF-I signaling, which contributes to muscle hypertrophy and atrophy inhibition.
The compounds reduce adiposity, fasting blood glucose, plasma leptin, cholesterol, and triglycerides, as well as increase energy expenditure and improve muscle strength.
The compounds demonstrate dose-dependent efficacy in increasing skeletal muscle mass and reducing fat without raising liver or kidney toxicity markers.
Certain compounds (e.g., betulinic acid, tomatidine) are more potent than ursolic acid in reducing muscle atrophy.
The compounds can be administered in combination with other anabolic or metabolic agents for enhanced therapeutic effects.
Documented Applications
Methods for treating muscle atrophy in mammals, fish, or birds by administering effective amounts of specified compounds or analogs.
Methods for promoting muscle health, normal muscle function, and healthy aging muscles by administering effective amounts of compounds.
Methods to enhance muscle formation, increase muscle mass, and reduce muscle atrophy in animals including humans and domesticated animals.
Methods for lowering blood glucose in animals using ursolic acid, naringenin analogs, hippeastrine, and conessine analogs.
Pharmaceutical compositions comprising the disclosed compounds for treatment or prevention of muscle atrophy and associated metabolic disorders.
Identification methods for compounds that inhibit muscle atrophy by modulating expression of muscle atrophy signature mRNAs.
Use of compounds as pharmacological tools for developing test systems for muscle atrophy inhibitors in laboratory animals.
Kits comprising the disclosed compounds and agents for treating or preventing muscle atrophy, with instructions and optional anabolic agents.
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