α‐Cedrene, a Newly Identified Ligand of MOR23, Increases Skeletal Muscle Mass and Strength

SCOPE: Skeletal muscle atrophy is a common and debilitating condition that lacks an effective therapy. In this study, the effects of α-cedrene are tested, a natural ligand of mouse olfactory receptor 23 (MOR23) whose ectopic function regulating myogenesis on skeletal muscle growth was reported recently. METHODS AND RESULTS: α-Cedrene not only stimulated hypertrophy but also attenuated free fatty acid-induced atrophy of cultured skeletal myotubes, as evidenced by an increased myotube diameter, fusion index, and total cellular protein content. These hypertrophic and antiatrophic properties of α-cedrene in cultured myotubes were confirmed in corresponding mouse models. The skeletal muscle mass, total muscle protein content, average cross-sectional area of myofibers, and muscle strength were significantly greater in α-cedrene-treated mice compared with untreated animals during either a regular chow diet or high-fat diet. Receptor knockdown experiments using RNA interference in cultured skeletal myotubes revealed that the hypertrophic and antiatrophic properties of α-cedrene may be mediated by MOR23. Furthermore, α-cedrene induced the expression of MOR23 and enhanced its downstream cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cyclic AMP-responsive element-binding protein (CREB) signaling in the skeletal muscle of mice fed chow or high-fat diet. CONCLUSIONS: α-Cedrene is a promising agent that may be applied to enhance the mass and strength of skeletal muscle.