GSE133505
RNA-Seq of Myf6-knockout versus Wild-type satellite cells
In metazoans, skeletal muscle evolved to contract and produce force.  Recent experimental evidence, however, suggests  that  skeletal muscle has also acquired  endocrine functions and produces a vast array of muscle-derived cytokines  and growth  factors, collectively  called myokines. The mechanisms that regulate myokine production and their effect on the resident stem cell population inskeletal muscle remain unknown. Here, we report that in adult skeletal muscle,  Myf6/MRF4  is a major regulator of myokine expression. Genetic  deletion  of  Myf6  in skeletal  muscle leads  to reduction of the muscle stem  cell (MuSCs)  pool  in  adult  mice  in  a myokine-dependent  manner  but,  surprisingly,  does  not  disrupt  muscle differentiation. Using ChIP-Seq and gene expression analyses of myogenic factors, we show that Myf6/MRF4 is a direct regulator of many myokines  and muscle-secreted  proteins,  including ligands  for  canonical signaling pathways such as EGFR and VEGFR.  Consequently, in Myf6-deficient animals,MuSCs increasingly break quiescence, but can nevertheless undergo differentiation. Lastly, we show that Myf6 and its gene network rapidly respondto aerobic and anaerobic exercise. Together, these findings indicate that control of myokine signaling by Myf6 is critical to maintain muscle stem cell pool and skeletal muscle function via myokine signaling. Overall design: Satellite cells from two 10 month-old female wild-type mice, two 10 month-old female Myf6-knockout mice and three 4 week-old male wild-type mice were analyzed.