Myomaker, and Myomixer-Myomerger-Minion modulate the efficiency of skeletal muscle development with melatonin supplementation through Wnt/β-catenin pathway

Melatonin, a pleiotropic hormone secreted from the pineal gland, has been shown to exert beneficial effects in muscle regeneration and repair due to its functional diversity, including anti-inflammation, anti-apoptosis, and anti-oxidative activity. However, little is known about the negative role of melatonin in myogenesis. Here, using skeletal muscle cells, we found that melatonin promoted C2C12 cells proliferation and inhibits differentiation both in C2C12 cells and primary myoblasts in mice. Melatonin administration significantly down-regulated differentiation and fusion related genes and inhibited myotube formation both in C2C12 cells and primary myoblasts in mice. RNA-seq showed that melatonin down-regulated essential fusion pore components Myomaker and Myomixer-Myomerger-Minion. Moreover, melatonin suppressed Wnt/beta-catenin signaling. Inhibition of GSK3 beta by LiCl rescued the influence of melatonin on differentiation efficiency, Myomaker, but not Myomxier in C2C12 cells. In conclusion, melatonin inhibits myogenic differentiation, Myomaker, and Myomixer through reducing Wnt/beta-catenin signaling. These data establish a link between melatonin and fusogenic membrane proteins Myomaker and Myomixer, and suggest the new perspective of melatonin in treatment or preventment of muscular diseases.