Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.
Core Facility of The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.
Eur J Pharmacol. 2023 Nov 15;959:176085. doi: 10.1016/j.ejphar.2023.176085. Epub 2023 Oct 6.
Despite the great clinical benefits of statins in cardiovascular diseases, their widespread use may lead to adverse muscle reactions associated with mitochondrial dysfunction. Some studies have demonstrated that statins provide substantial improvement to skeletal muscle health in mice. Our previous study found that oral treatment with atorvastatin (Ator, 3 mg/kg) protected myocardial mitochondria in high-fat diet (HFD)-fed mice. Therefore, this study aimed to explore the influence of low-dose Ator (3 mg/kg) on mitochondria in skeletal muscle under cholesterol overload. Male C57BL/6J mice were fed a HFD for 18 weeks and orally administered Ator (3 mg/kg) during the last 12 weeks. Ator treatment had no effects on elevated serum cholesterol and glucose levels in HFD-fed mice. Serum creatine kinase levels and the cross-sectional area of muscle cells were not affected by HFD feeding or Ator treatment. Increased expression of PINK1-LC3 II (activated mitophagy), MFN2 (fusion), and PGC-1α (biogenesis) proteins was induced in the skeletal muscles of HFD-fed mice. Treatment with Ator inhibited PINK1 and LC3 II protein expression, but further promoted MFN1, MFN2, and OPA1 expression. The impairments in mitochondrial quality and morphology in HFD-fed mice were attenuated by treatment with Ator. Furthermore, Ator treatment enhanced glucose oxidation capacity and restored ATP production in the skeletal muscles of HFD-fed mice. The study reveals that low-dose Ator has a protective effect on muscle mitochondria in mice, likely through inhibiting mitophagy and enhancing mitochondrial fusion. This suggests that skeletal muscle mitochondria may be one of low-dose Ator-mediated protective targets.
尽管他汀类药物在心血管疾病中有很大的临床益处，但它们的广泛使用可能会导致与线粒体功能障碍相关的不良肌肉反应。一些研究表明，他汀类药物可显著改善小鼠的骨骼肌健康。我们之前的研究发现，阿托伐他汀（Ator，3mg/kg）口服治疗可保护高脂饮食（HFD）喂养小鼠的心肌线粒体。因此，本研究旨在探讨低剂量阿托伐他汀（3mg/kg）在胆固醇过载下对骨骼肌线粒体的影响。雄性 C57BL/6J 小鼠喂养 HFD 18 周，并在最后 12 周给予阿托伐他汀（3mg/kg）口服治疗。阿托伐他汀治疗对 HFD 喂养小鼠升高的血清胆固醇和葡萄糖水平没有影响。血清肌酸激酶水平和肌细胞横截面积不受 HFD 喂养或阿托伐他汀治疗的影响。在 HFD 喂养小鼠的骨骼肌中，诱导了 PINK1-LC3 II（激活的自噬）、MFN2（融合）和 PGC-1α（生物发生）蛋白的高表达。阿托伐他汀抑制了 PINK1 和 LC3 II 蛋白的表达，但进一步促进了 MFN1、MFN2 和 OPA1 的表达。阿托伐他汀治疗减轻了 HFD 喂养小鼠线粒体质量和形态的损伤。此外，阿托伐他汀治疗增强了 HFD 喂养小鼠骨骼肌的葡萄糖氧化能力并恢复了 ATP 产生。研究揭示，低剂量阿托伐他汀对小鼠骨骼肌线粒体具有保护作用，可能通过抑制自噬和增强线粒体融合。这表明骨骼肌线粒体可能是低剂量阿托伐他汀介导的保护靶标之一。
