5-Heptadecylresorcinol Ameliorates Obesity-Associated Skeletal Muscle Mitochondrial Dysfunction through SIRT3-Mediated Mitophagy
Ziyuan Wang, Qing Li, Haihong Yang, Dandan Zhang, Yiman Zhang, Jing Wang, Jie Liu
Abstract
Skeletal muscle dysfunction caused by obesity is characterized by the decline in mitochondrial content and function. 5-Heptadecylresorcinol (AR-C17) is a specific bioactive component derived from whole wheat and rye, which has been evidenced to improve obesity-associated skeletal muscle dysregulation. However, the mechanism underlying its protective activity requires further exploration. Herein, we found that AR-C17 (5, 10, and 20 μM) intervention reversed PA-induced (0.5 mM) reduction in mitochondrial content, mitochondrial membrane potential, and mitochondrial energy metabolism in C2C12 cells. Meanwhile, AR-C17 evidently alleviated PA-mediated myotube mitochondrial dysfunction via elevating mitochondria autophagy flux and upregulating the expression level of autophagy-related protein, while this effect was abolished by an autophagy inhibitor (3-MA). Further analysis showed that SIRT3-FOXO3A-PINK-Parkin-mediated mitophagy was involved in the modulation of myocyte mitochondrial dysfunction by AR-C17. In addition, AR-C17 administration (30 and 150 mg/kg/day) significantly improved high-fat-diet-induced mitochondrial dysregulation in mice skeletal muscle tissue via SIRT3-dependent mitophagy. Our findings indicate that skeletal muscle cells are responsive to AR-C17, which improves myogenesis and mitophagy in vitro and in vivo.