Abstract
Dysfunction of muscle satellite cells is linked to diabetic myopathy. The mechanisms vitiating muscle satellite cell proliferative activity in diabetes are not well understood. Here, we show that AS160, a key cytosolic Rab-GTPase activating protein (RabGAP) in insulin signaling, is a moonlighting protein regulating muscle satellite cell proliferation as a transcriptional co-factor. Deletion of AS160, but not its GAP-inactive mutation, impairs muscle satellite cell proliferation and consequent muscle regeneration, and exacerbates age-related sarcopenia. Mechanistically, Thr642 phosphorylation of AS160 promotes its translocation into the nucleus where AS160 functions as a co-factor of Signal Transducer and Activator of Transcription 3 (STAT3). AS160 binds to STAT3 to enhance the transcription of myogenic cascades and consequent muscle satellite cell proliferation. Disruption of the AS160-STAT3 interaction, or inhibition of AS160-Thr642 phosphorylation, inhibits muscle satellite cell proliferation and impairs muscle regeneration. Together, our findings reveal a moonlighting function of AS160 as a transcriptional co-factor in the nucleus, and have therapeutic implications for muscle regeneration.