Obesity Impairs Skeletal Muscle Regeneration Through Inhibition of AMPK

Obesity is increasing rapidly worldwide and is accompanied by many complications, including impaired muscle regeneration. The obese condition is known to inhibit AMPK activity in multiple tissues. We hypothesized that the loss of AMPK activity is a major reason for hampered muscle regeneration in obese subjects. We found that obesity inhibits AMPK activity in regenerating muscle, which was associated with impeded satellite cell activation and impaired muscle regeneration. To test the mediatory role of AMPK alpha 1, we knocked out AMPK alpha 1 and found that both proliferation and differentiation of satellite cells are reduced after injury and that muscle regeneration is severely impeded, reminiscent of hampered muscle regeneration seen in obese subjects. Transplanted satellite cells with AMPK alpha 1 deficiency had severely impaired myogenic capacity in regenerating muscle fibers. We also found that attenuated muscle regeneration in obese mice is rescued by AICAR, a drug that specifically activates AMPK, but AICAR treatment failed to improve muscle regeneration in obese mice with satellite cell-specific AMPK alpha 1 knockout, demonstrating the importance of AMPK alpha 1 in satellite cell activation and muscle regeneration. In summary, AMPK alpha 1 is a key mediator linking obesity and impaired muscle regeneration, providing a convenient drug target to facilitate muscle regeneration in obese populations.