Roles of Oncostatin M and JAK/STAT pathway in myoblast differentiation, skeletal muscle regeneration, and skeletal muscle hypertrophy

Oncostatin M (OSM) is a cytokine of the interleukin-6 family and plays important roles during inflammation. However, its roles in myoblast differentiation and muscle regeneration remain unexplored. We showed here that OSM potently inhibits myoblast differentiation mainly by activating the JAK1/STAT1/STAT3 pathway. OSM downregulates MEF2A, upregulates the expression of Id1 and Id2, and inhibits the transcriptional activity of MyoD and MEF2. In addition, OSM also enhances the expression of STAT3 and OSM receptor, which constitutes a positive feedback loop to further amplify OSM-induced signaling. Moreover, we found that STAT1 physically associates with MEF2 and represses its transcriptional activity, which could account for the OSM-mediated repression of MEF2. Although undetectable in normal muscles, OSM is rapidly induced upon injury and then promptly downregulated just before the majority of myoblasts differentiate. Prolonged expression of OSM in muscles compromised the regeneration process without affecting myoblast proliferation, suggesting that OSM functions to prevent proliferating myoblasts from premature differentiation during the early phase of muscle regeneration.;STAT3 is abundantly expressed in skeletal muscles and is involved in the proliferation of myoblasts. However, its role in vivo during muscle regeneration and hypertrophy has not been explored mainly due to the early lethality of STAT3-/- mice. To overcome this problem, STAT3 is specifically deleted in skeletal muscle by crossing STAT3 flox/flox mice with Cre-expressing mice under the control of the pax7 or myf5 promoter. Both Cre lines resulted in the deletion of STAT3 specifically and efficiently in skeletal muscles and primary myoblasts. Next, we found that the loss of STAT3 leads to inhibition of satellite cells-mediated compensatory muscle hypertrophy. In addition, MyoD and myogenin expression was decreased in the STAT3 deficient mice. Further investigation of the primary myoblasts from STAT3 deficient mice showed that the loss of STAT3 compromised the proliferation of myoblasts and down-regulated c-Myc. Taken together, these results here indicated that STAT3 is an essential regulator in satellite cells- mediated muscle hypertrophy.