Dana-Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Cell Metab. 2011 Feb 2;13(2):160-9. doi: 10.1016/j.cmet.2011.01.003.
Exercise has been shown to be effective for treating obesity and type 2 diabetes. However, the molecular mechanisms for adaptation to exercise training are not fully understood. Endoplasmic reticulum (ER) stress has been linked to metabolic dysfunction. Here we show that the unfolded protein response (UPR), an adaptive response pathway that maintains ER homeostasis upon luminal stress, is activated in skeletal muscle during exercise and adapts skeletal muscle to exercise training. The transcriptional coactivator PGC-1α, which regulates several exercise-associated aspects of skeletal muscle function, mediates the UPR in myotubes and skeletal muscle through coactivation of ATF6α. Efficient recovery from acute exercise is compromised in ATF6α(-/-) mice. Blocking ER-stress-related cell death via deletion of CHOP partially rescues the exercise intolerance phenotype in muscle-specific PGC-1α KO mice. These findings suggest that modulation of the UPR through PGC1α represents an alternative avenue to improve skeletal muscle function and achieve metabolic benefits.
运动已被证明对治疗肥胖和 2 型糖尿病有效。然而，运动训练适应的分子机制尚未完全了解。内质网（ER）应激与代谢功能障碍有关。在这里，我们表明，未折叠蛋白反应（UPR）是一种适应性反应途径，可在腔内质网应激时维持 ER 稳态，在运动期间被激活，并使骨骼肌适应运动训练。转录共激活因子 PGC-1α 调节骨骼肌功能的几个与运动相关的方面，通过共激活 ATF6α 介导肌管和骨骼肌中的 UPR。急性运动后恢复效率在 ATF6α(-/-) 小鼠中受损。通过 CHOP 的缺失阻断 ER 应激相关细胞死亡部分挽救了肌肉特异性 PGC-1α KO 小鼠的运动不耐受表型。这些发现表明，通过 PGC1α 调节 UPR 代表了改善骨骼肌功能和获得代谢益处的另一种途径。
