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.