Effects of ursolic acid on sub-lesional muscle pathology in a contusion model of spinal cord injury

• Published in: PloS one 2018-08, Vol.13 (8), p.e0203042
• Main Authors: Bigford, Gregory E, Darr, Andrew J, Bracchi-Ricard, Valerie C, Gao, Han, Nash, Mark S, Bethea, John R
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Acids; AKT protein; Analysis; Animals; Atrophy; Biology and Life Sciences; Care and treatment; Coordination; Disease Models, Animal; Female; FOXO1 protein; Gene Expression - drug effects; Genes; Genetic regulation; Genetic transformation; Genomics; Glucose; Glycolysis; Hypertrophy; Insulin resistance; Insulin-like growth factors; Intermediates; Laboratory animals; Medicine; Medicine and Health Sciences; Metabolism; Mice, Inbred C57BL; Motor Skills - drug effects; Muscle Strength - drug effects; Muscle, Skeletal - drug effects; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Muscles; Musculoskeletal system; Organ Size; Paralysis; Pathology; Patient outcomes; Protective Agents - pharmacology; Random Allocation; Research and Analysis Methods; Signaling; Skeletal muscle; Spinal cord injuries; Spinal Cord Injuries - drug therapy; Spinal Cord Injuries - pathology; Spinal Cord Injuries - physiopathology; Surgery; TOR protein; Transformation; Triterpenes - pharmacology; Ursolic Acid
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0203042

Spinal Cord Injury (SCI) results in severe sub-lesional muscle atrophy and fiber type transformation from slow oxidative to fast glycolytic, both contributing to functional deficits and maladaptive metabolic profiles. Therapeutic countermeasures have had limited success and muscle-related pathology remains a clinical priority. mTOR signaling is known to play a critical role in skeletal muscle growth and metabolism, and signal integration of anabolic and catabolic pathways. Recent studies show that the natural compound ursolic acid (UA) enhances mTOR signaling intermediates, independently inhibiting atrophy and inducing hypertrophy. Here, we examine the effects of UA treatment on sub-lesional muscle mTOR signaling, catabolic genes, and functional deficits following severe SCI in mice. We observe that UA treatment significantly attenuates SCI induced decreases in activated forms of mTOR, and signaling intermediates PI3K, AKT, and S6K, and the upregulation of catabolic genes including FOXO1, MAFbx, MURF-1, and PSMD11. In addition, UA treatment improves SCI induced deficits in body and sub-lesional muscle mass, as well as functional outcomes related to muscle function, motor coordination, and strength. These findings provide evidence that UA treatment may be a potential therapeutic strategy to improve muscle-specific pathological consequences of SCI.