It is controversial whether mitochondrial dysfunction in skeletal muscle is the cause or consequence of metabolic disorders. Herein, we demonstrate that in vivo inhibition of mitochondrial ATP synthase in muscle alters whole‐body lipid homeostasis. Mice with restrained mitochondrial ATP synthase activity presented intrafiber lipid droplets, dysregulation of acyl‐glycerides, and higher visceral adipose tissue deposits, poising these animals to insulin resistance. This mitochondrial energy crisis increases lactate production, prevents fatty acid β‐oxidation, and forces the catabolism of branched‐chain amino acids (BCAA) to provide acetyl‐CoA for de novo lipid synthesis. In turn, muscle accumulation of acetyl‐CoA leads to acetylation‐dependent inhibition of mitochondrial respiratory complex II enhancing oxidative phosphorylation dysfunction which results in augmented ROS production. By screening 702 FDA‐approved drugs, we identified edaravone as a potent mitochondrial antioxidant and enhancer. Edaravone administration restored ROS and lipid homeostasis in skeletal muscle and reinstated insulin sensitivity. Our results suggest that muscular mitochondrial perturbations are causative of metabolic disorders and that edaravone is a potential treatment for these diseases.

中文翻译：

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功能失调的氧化磷酸化使支链氨基酸分解代谢分流到骨骼肌的脂肪形成中。

骨骼肌线粒体功能障碍是代谢紊乱的原因还是后果，一直存在争议。本文中，我们证明了体内对肌肉中线粒体ATP合酶的抑制作用会改变全身脂质的体内平衡。线粒体ATP合酶活性受抑制的小鼠出现纤维内脂质滴，酰基甘油酯失调和内脏脂肪组织沉积增加，使这些动物对胰岛素抵抗具有抵抗力。线粒体能量危机增加了乳酸的产生，阻止了脂肪酸β-氧化，并迫使分支链氨基酸（BCAA）的分解代谢提供了从头开始的乙酰-CoA。脂质合成。反过来，乙酰辅酶A的肌肉蓄积会导致线粒体呼吸复合物II的乙酰化依赖性抑制，从而增强氧化磷酸化功能障碍，从而导致ROS产生增加。通过筛选702种FDA批准的药物，我们确定了依达拉奉是有效的线粒体抗氧化剂和增强剂。依达拉奉给药可恢复骨骼肌中的ROS和脂质稳态，并恢复胰岛素敏感性。我们的结果表明，肌肉线粒体微扰是代谢紊乱的原因，依达拉奉是这些疾病的潜在治疗方法。