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-10668087-B2
Publication Date
2020-06-02
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 providing to an animal in need an effective amount of a compound that modulates the 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.
The problem being solved is the lack of medical therapies to prevent or reverse skeletal muscle atrophy in human patients. Muscle atrophy is associated with numerous conditions such as starvation, aging, cancer, chronic renal failure, congestive heart failure, chronic respiratory disease, insulin deficiency, acute critical illness, chronic infections including HIV/AIDS, muscle denervation, and various medical and surgical conditions that limit muscle use. These conditions lead to serious health consequences including weakness, falls, fractures, infections, and loss of independence, imposing a significant burden on individuals and society.
The invention addresses the scarcity of compounds that are potent, efficacious, and selective modulators of muscle growth effective in treating muscle atrophy and diseases involving muscle loss or the need to increase muscle mass. Through the identification of muscle atrophy signatures comprising induced and repressed mRNAs during muscle atrophy, the invention provides compounds that down regulate multiple induced mRNAs and/or up regulate multiple repressed mRNAs of these signatures, thereby inhibiting muscle atrophy. Additionally, the invention includes methods for identifying compounds suitable for this purpose by assessing their effect on the expression levels of these mRNAs.
Claims Coverage
The patent includes multiple independent claims focusing on methods for treating muscle atrophy and related conditions using specific compounds and dosages.
Methods for increasing skeletal muscle mass and reducing muscle atrophy
A method for increasing skeletal muscle mass, reducing skeletal muscle atrophy, increasing muscular strength, promoting muscle growth, decreasing muscle wasting, or increasing strength per unit of muscle mass in an animal by administering an effective amount of one or more compounds or their stereoisomers, tautomers, solvates, or pharmaceutically acceptable salts.
Use of specific compounds and dosages in muscle atrophy treatment
The method involves administering compounds selected from tacrine analogs, naringenin analogs, allantoin analogs, conessine analogs, tomatidine analogs, ungerine/hippeastrine analogs, and betulinic acid analogs, or mixtures thereof, at doses greater than specified milligram amounts per day or per kilogram of body weight in various animal subjects.
Applicability to a range of animal species
The method is applicable to animals including non-human primates, domesticated fish, crustaceans, mollusks, poultry, dogs, cats, livestock, and others, addressing muscle mass improvement and atrophy reduction across species.
The claims cover methods of using specific triterpenoid and related compounds to treat muscle atrophy and promote muscle growth, detailing precise compounds, dosages, and target animal species, establishing a comprehensive scope for muscle health therapeutic interventions.
Stated Advantages
Inhibiting muscle atrophy.
Promoting muscle health, normal muscle function, and healthy aging muscles.
Increasing skeletal muscle mass and muscular strength.
Reducing adiposity, fasting blood glucose, plasma leptin, cholesterol and triglycerides.
Increasing energy expenditure and brown fat relative to white fat.
Ursolic acid and other compounds enhance skeletal muscle IGF-I expression and signaling, thereby reducing atrophy-associated gene expression and promoting hypertrophy.
Documented Applications
Treatment of muscle atrophy associated with conditions such as malnutrition, muscle disuse, neurologic diseases including multiple sclerosis, amyotrophic lateral sclerosis, spinal muscular atrophy, critical illness neuropathy, spinal cord injury, orthopedic injury, casting, chronic diseases including cancer, congestive heart failure, chronic respiratory and renal diseases, diabetes mellitus, hormonal deficiencies, chronic infections such as HIV/AIDS and tuberculosis, burns, sepsis, mechanical ventilation-related muscle loss, drug-induced myopathy, genetic and autoimmune muscular diseases, spaceflight-induced atrophy, and age-related sarcopenia.
Methods to promote muscle health, normal muscle function, and healthy aging muscles in mammals and other animals.
Methods to reduce body fat, blood glucose, blood triglycerides, blood cholesterol, obesity, fatty liver disease and diabetes.
Pharmaceutical compositions and kits comprising compounds for treating muscle atrophy and metabolic disorders.
Methods of identifying compounds that inhibit muscle atrophy by assessing modulation of muscle atrophy signature mRNA levels.
Use of compounds to enhance muscle formation and facilitate tissue formation in vitro.
Methods for lowering blood glucose levels in animals using ursolic acid, naringenin, hippeastrine, and conessine analogs.
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