Wang Ping, Li Jiaxin, Li Chun Guang, Zhou Xian, Chen Xiaolong, Zhu Minghua, Wang Hongjiang
School of Physical Education, Hangzhou Normal University, Hangzhou, China.
NICM Health Research Institute, Western Sydney University, Westmead, New South Wales, Australia.
Clin Exp Pharmacol Physiol. 2025 Mar;52(3):e70010. doi: 10.1111/1440-1681.70010.
Exercise activates autophagy and lysosome system in skeletal muscle, which are known to play an important role in metabolic adaptation. However, the mechanism of exercise-activated autophagy and lysosome system in obese insulin resistance remains covert. In this study, we investigated the role of exercise-induced activation of autophagy and lysosome system in improving glucose metabolism of skeletal muscle. Male C57BL/6 mice were randomly divided into five groups: the chow diet (CD) group, the high-fat diet (HFD) group, the high-fat diet plus exercise (HFD-E) group and the HFD-E treated with calcineurin inhibitor FK506 (HFD-E-F) or saline (HFD-E-S) groups. The mice in exercise groups (HFD-E, HFD-E-F and HFD-E-S) were subjected to aerobic treadmill exercise (speed at 12 m/min for 1 h per session, 0° slope, 5 days per week for 12 weeks). Mice of HFD-E-F group were intraperitoneally administered FK506 (1 mg/kg), once each day for 2 weeks before the end of exercise. Expressions pTFEB, T-TFEB and autophagy-lysosome markers, including Beclin1, LC3, ULK1, SQSTM1, LAMP1, CTSD and CTSL proteins in gastrocnemius muscle were analysed. We demonstrated that HFD induced insulin resistance and decreased autophagy-lysosomal proteins and the exercise significantly increased transcription factor EB (TFEB) translocation from the cytoplasm to the nucleus, restored the impaired autophagy-lysosomal-related protein expressions, and improved glucose metabolism. The increase in TFEB nuclear translocation was partly blocked by the calcineurin inhibitor FK506. Our results suggest that exercise promotes autophagy and lysosome restoration by regulating calcineurin-mediated TFEB nuclear translocation, ultimately alleviating HFD-induced insulin resistance in mice skeletal muscle.
运动可激活骨骼肌中的自噬和溶酶体系统，已知这两个系统在代谢适应中发挥重要作用。然而，运动激活自噬和溶酶体系统在肥胖胰岛素抵抗中的机制仍不清楚。在本研究中，我们调查了运动诱导的自噬和溶酶体系统激活在改善骨骼肌葡萄糖代谢中的作用。雄性C57BL/6小鼠被随机分为五组：正常饮食（CD）组、高脂饮食（HFD）组、高脂饮食加运动（HFD-E）组以及用钙调神经磷酸酶抑制剂FK506处理的HFD-E（HFD-E-F）组或用生理盐水处理的HFD-E（HFD-E-S）组。运动组（HFD-E、HFD-E-F和HFD-E-S）的小鼠进行有氧跑步机运动（速度为12米/分钟，每次1小时，坡度为0°，每周5天，共12周）。HFD-E-F组的小鼠在运动结束前2周每天腹腔注射FK506（1毫克/千克）。分析了腓肠肌中pTFEB、T-TFEB以及自噬-溶酶体标志物（包括Beclin1、LC3、ULK1、SQSTM1、LAMP1、CTSD和CTSL蛋白）的表达。我们证明，高脂饮食诱导胰岛素抵抗并降低自噬-溶酶体蛋白水平，而运动显著增加转录因子EB（TFEB）从细胞质向细胞核的转位，恢复受损的自噬-溶酶体相关蛋白表达，并改善葡萄糖代谢。钙调神经磷酸酶抑制剂FK506部分阻断了TFEB核转位的增加。我们的结果表明，运动通过调节钙调神经磷酸酶介导的TFEB核转位促进自噬和溶酶体恢复，最终减轻高脂饮食诱导的小鼠骨骼肌胰岛素抵抗。
