5-Heptadecylresorcinol Ameliorates Obesity-Associated Skeletal Muscle Mitochondrial Dysfunction through SIRT3-Mediated Mitophagy

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.

5-heptadecylresorcinol; SIRT3; mitochondrial function; mitophagy; skeletal muscle.