STAT3 inhibition recovers regeneration of aged muscles by restoring autophagy in muscle stem cells

Age-related reduction in muscle stem cells (MuSCs) regenerative capacity is associated with cell-autonomous and non-cell autonomous changes caused by alterations of systemic and skeletal muscle environments, ultimately leading to a decline in MuSC number and function. Previous studies demonstrated that STAT3 plays a key role in driving MuSCs expansion and differentiation following injury-activated regeneration, by regulating autophagy in activated MuSCs. However, autophagy gradually declines in MuSCs during lifespan and contributes to the impairment of MuSC-mediated regeneration of aged muscles. Here we show that STAT3 inhibition restores the autophagic process in aged MuSCs, thereby recovering MuSC ability to promote muscle regeneration in geriatric mice. We show that STAT3 inhibition could activate autophagy at nuclear level, by promoting transcription of autophagy-related genes, as well as at the cytoplasmic level, by targeting STAT3/PKR-phosphorylation of eIF2α. These results point to STAT3 inhibition as a potential intervention to reverse the age-related autophagic block that impairs MuSC ability to regenerate aged muscles. They also reveal that STAT3 regulates MuSC function by both transcription-dependent and independent regulation of autophagy.