Nuclear entry of AS160 as a transcriptional regulator of satellite cells for muscle regeneration

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.