Obesity Impairs Skeletal Muscle Regeneration Through Inhibition of AMPK.
Obesity Impairs Skeletal Muscle Regeneration Through Inhibition of AMPK.
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作者：
Fu X;Zhu M;Zhang S;Foretz M;Viollet B;Du M
肥胖在世界范围内迅速增加，并伴有许多并发症，包括肌肉再生受损。已知肥胖状况会抑制多种组织中的AMPK活性。我们假设AMPK活性的丧失是肥胖受试者肌肉再生受阻的主要原因。我们发现肥胖抑制再生肌肉中的AMPK活性，这与卫星细胞激活受阻和肌肉再生受损有关。为了测试AMPKα1的调节作用，我们敲除AMPKα1，发现损伤后卫星细胞的增殖和分化都减少，肌肉再生受到严重阻碍，与肥胖受试者的肌肉再生受阻相似。缺乏AMPKα1的移植卫星细胞再生肌纤维的能力严重受损。我们还发现，肥胖小鼠的肌肉再生被AICAR（一种特异性激活AMPK的药物）所挽救，但AICAR治疗未能改善卫星细胞特异性AMPKα1敲除的肥胖小鼠的肌肉再生，这表明AMPKα1在卫星细胞激活和肌肉再生中的重要性。综上所述，AMPKα1是连接肥胖和肌肉再生受损的关键介质，为肥胖人群促进肌肉再生提供了方便的药物靶点。
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 AMPKα1, we knocked out AMPKα1 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 AMPKα1 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 AMPKα1 knockout, demonstrating the importance of AMPKα1 in satellite cell activation and muscle regeneration. In summary, AMPKα1 is a key mediator linking obesity and impaired muscle regeneration, providing a convenient drug target to facilitate muscle regeneration in obese populations.