Research Fellow National Center of Neurology and Psychiatry (NCNP), Japan
Abstract: Elucidating the mechanisms of skeletal myogenesis is crucial for clarifying the pathophysiology of muscular disorders and facilitating muscle regeneration after injury. Enhancer of Zeste Homologue 2 (EZH2) is a catalytic subunit of Polycomb Repressive Complex 2 that regulates stem cell differentiation via transcriptional repression. In myoblasts, EZH2 contributes to maintaining the chromatin of muscle genes in a repressed state, whereas its downregulation leads to the transcriptional activation of the myogenic program. However, the precise mechanism of triggering this EZH2 downregulation after muscle injury remains unclear. Here, we show that serglycin promotes skeletal muscle regeneration through EZH2 degradation in myoblasts. We found CD90-positive human urine-derived cells (UDCs), which we previously reported as a cell population with a high potential for myogenic differentiation, excreted more serglycin than CD90-negative UDCs. Adding recombinant human serglycin to the culture medium significantly enhanced the fusion index of MYOD1-converted UDCs compared to untreated ones. Moreover, our immunoblotting data showed that serglycin activated the CD44-p38-EZH2 pathway, resulting in EZH2 degradation by phosphorylation of threonine 372. As a next step, to confirm whether serglycin could activate the same pathway in mouse myoblasts and promote muscle differentiation, we intramuscularly injected serglycin into the injured muscles of wild-type mice. As a result, in serglycin-injected mice, the percentage of embryonic myosin heavy chain positive fibers evaluated by immunohistochemistry showed its peak on day 5 which was earlier than day 8 in the control group. Simultaneously, serglycin-injected mice indicated significantly high muscle torque both on days 5 and 8 compared to the control group. Taken together, serglycin can enhance regeneration in injured muscles by degrading EZH2 in myoblasts. Our findings should pave the way for developing regenerative medicine approaches using serglycin to mitigate skeletal muscle disorders.
