Department of Emergency, Cardinal Tien Hospital, New Taipei City, Taiwan.
Department of Physiology and Biophysics, Graduate Institute of Physiology, National Defense Medical Center, Taipei, Taiwan.
Eur J Pharmacol. 2024 Sep 15;979:176854. doi: 10.1016/j.ejphar.2024.176854. Epub 2024 Jul 25.
Obesity-induced muscle atrophy leads to physical impairment and metabolic dysfunction, which are risky for older adults. The activity of pyruvate dehydrogenase (PDH), a critical regulator of glucose metabolism, is reduced in obesity. Additionally, PDH activator dichloroacetate (DCA) improves metabolic dysfunction. However, the effects of PDH activation on skeletal muscles in obesity remain unclear. Thus, this study aimed to evaluate the effects of PDH activation by DCA treatment on obesity-induced muscle atrophy in vitro and in vivo and elucidate the possible underlying mechanisms. Results showed that PDH activation by DCA treatment ameliorated muscle loss, decreased the cross-sectional area, and reduced grip strength in C57BL/6 mice fed a high-fat diet (HFD). Elevation of muscle atrophic factors atrogin-1 and muscle RING-finger protein-1 (MuRF-1) and autophagy factors LC3BII and p62 were abrogated by DCA treatment in palmitate-treated C2C12 myotubes and in the skeletal muscles of HFD-fed mice. Moreover, p-Akt, p-FoxO1, and p-FoxO3 protein levels were reduced and p-NF-κB p65 and p-p38 MAPK protein levels were elevated in palmitate-treated C2C12 myotubes, which were restored by DCA treatment. However, the protective effects of DCA treatment against myotube atrophy were reversed by treatment with Akt inhibitor MK2206. Taken together, our study demonstrated that PDH activation by DCA treatment can alleviate obesity-induced muscle atrophy. It may serve as a basis for developing novel strategies to prevent obesity-associated muscle loss.
肥胖导致的肌肉萎缩会导致身体机能障碍和代谢功能紊乱，这对老年人来说是很危险的。丙酮酸脱氢酶（PDH）是葡萄糖代谢的关键调节因子，其活性在肥胖中降低。此外，PDH 激活剂二氯乙酸（DCA）可改善代谢功能障碍。然而，PDH 激活对肥胖症骨骼肌的影响尚不清楚。因此，本研究旨在评估 DCA 处理对体外和体内肥胖诱导的肌肉萎缩的影响，并阐明可能的潜在机制。结果表明，DCA 处理激活 PDH 可改善肌肉损失，减小横截面面积，并降低高脂肪饮食（HFD）喂养的 C57BL/6 小鼠的握力。DCA 处理可消除棕榈酸处理的 C2C12 肌管和 HFD 喂养小鼠骨骼肌中肌肉萎缩因子 atrogin-1 和肌肉环指蛋白-1（MuRF-1）以及自噬因子 LC3BII 和 p62 的升高。此外，棕榈酸处理的 C2C12 肌管中 p-Akt、p-FoxO1 和 p-FoxO3 蛋白水平降低，p-NF-κB p65 和 p-p38 MAPK 蛋白水平升高，而 DCA 处理可恢复这些蛋白水平。然而，Akt 抑制剂 MK2206 可逆转 DCA 处理对肌管萎缩的保护作用。综上所述，本研究表明，DCA 处理激活 PDH 可减轻肥胖引起的肌肉萎缩。它可能为开发预防肥胖相关肌肉丢失的新策略提供依据。
