Mutations in dysferlin are responsible for a group of progressive, recessively inherited muscular dystrophies known as dysferlinopathies. Using recombinant proteins and affinity purification methods combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), we found that AMP-activated protein kinase (AMPK)γ1 was bound to a region of dysferlin located between the third and fourth C2 domains. Using ex vivo laser injury experiments, we demonstrated that the AMPK complex was vital for the sarcolemmal damage repair of skeletal muscle fibers. Injury-induced AMPK complex accumulation was dependent on the presence of Ca2+, and the rate of accumulation was regulated by dysferlin. Furthermore, it was found that the phosphorylation of AMPKα was essential for plasma membrane repair, and treatment with an AMPK activator rescued the membrane-repair impairment observed in immortalized human myotubes with reduced expression of dysferlin and dysferlin-null mouse fibers. Finally, it was determined that treatment with the AMPK activator metformin improved the muscle phenotype in zebrafish and mouse models of dysferlin deficiency. These findings indicate that the AMPK complex is essential for plasma membrane repair and is a potential therapeutic target for dysferlinopathy.

中文翻译：

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AMPK复合物激活促进神经营养不良症的肌膜修复。

dysferlin中的突变是造成一组进行性，隐性遗传的肌营养不良症的原因，称为dysferlinopathies。使用重组蛋白和亲和纯化方法结合液相色谱-串联质谱（LC-MS / MS），我们发现AMP激活的蛋白激酶（AMPK）γ1绑定到dysferlin位于第三和第四C2域之间的区域。使用离体激光损伤实验，我们证明了AMPK复合物对于骨骼肌纤维的肌膜损伤修复至关重要。损伤诱导的AMPK复合物的积累取决于Ca2 +的存在，并且积累的速率受dysferlin的调节。此外，还发现AMPKα的磷酸化对于质膜修复至关重要，使用AMPK激活剂进行治疗，可以挽救在永生化的人肌管中观察到的膜修复受损，并减少了dysferlin和dysferlin-null小鼠纤维的表达。最后，已确定用AMPK激活剂二甲双胍治疗可改善斑马鱼和dysferlin缺乏症小鼠模型的肌肉表型。这些发现表明，AMPK复合物对于质膜修复是必不可少的，并且是dysferlinopathy的潜在治疗靶标。