Ursolic Acid Restores Redox Homeostasis and Pro-inflammatory Cytokine Production in Denervation-Induced Skeletal Muscle Atrophy.

Abstract

Skeletal muscle (SkM) atrophy results from metabolic disorders causing body and muscle mass loss, affecting morbidity and mortality. Increased oxidative stress, inflammation, and poor prognosis are the leading causes of involuntary weight loss. Ursolic acid (UA), known for its antioxidant and anti-inflammatory properties, can potentially reduce oxidative stress and inflammation in muscles, but its effects on muscle mass regulation are still unknown. Therefore, the present study investigated the medicinal efficacy of UA and its mode of action against the murine model of SkM atrophy over 7 days of UA supplementation. Denervation-induced SkM atrophy significantly impacts overall body weight and the weight of individual muscles (p < 0.05). However, supplementation with UA can effectively counteract these effects by promoting the synthesis of the slow-myosin heavy chain, thereby restoring body weight and myotube diameter. Moreover, UA also plays a crucial role in reducing the production levels of reactive oxygen species (ROS), lipid peroxidation (LPO), and caspase-3-like activity in atrophied muscles. UA also prevents the leakage of creatine kinase (CK) through the upregulation of superoxide dismutase (SOD) and glutathione peroxidase (GPx) expression. Furthermore, the results obtained from qRT-PCR demonstrated a significant decrease in the levels of pro-inflammatory markers, namely IL-1β, IL-6, TNF-α, and TWEAK, up to four-fold after the third day of the UA intervention. UA also upregulated PGC-1α, Bcl2, and p-Akt^ser473 expression towards the regulation of redox homeostasis.