Mitochondrial function in skeletal myofibers is controlled by a TRF2-SIRT3 axis over lifetime
Mitochondrial function in skeletal myofibers is controlled by a TRF2-SIRT3 axis over lifetime
复制标题
骨骼肌纤维中的线粒体功能在整个生命周期中由 TRF2-SIRT3 轴控制
DOI：
10.1111/acel.13097
复制
发表时间：
2020-01-28
期刊：
影响因子：
7.8
通讯作者：
Gilson, Eric
中科院分区：
文献类型：
--
作者：
Robin, Jerome D.;Burbano, Maria-Sol Jacome;Gilson, Eric
端粒缩短遵循一个发育调节的过程，导致分裂细胞的复制衰老。然而，端粒的变化是否涉及有丝分裂后细胞功能和衰老仍然是一个谜。在这项研究中，我们发现TRF 2蛋白（一种关键的端粒加帽蛋白）的水平在人类骨骼肌中随着寿命的推移而下降。在培养的人肌管中，TRF 2下调不会引发端粒功能障碍，但抑制线粒体Sirtuin 3基因（SIRT 3）的表达，导致线粒体呼吸功能障碍和活性氧水平增加。重要的是，恢复TRF 2受损肌管中的Sirt 3水平完全挽救了线粒体功能。最后，小鼠骨骼肌中TRF 2基因的靶向消融导致线粒体功能障碍和sirt 3下调，类似于TRF 2受损的人类肌管。总之，这些结果揭示了TRF 2-SIRT 3轴控制肌肉线粒体功能。我们建议，这轴连接发育调节端粒的变化，肌肉氧化还原代谢。
Telomere shortening follows a developmentally regulated process that leads to replicative senescence of dividing cells. However, whether telomere changes are involved in postmitotic cell function and aging remains elusive. In this study, we discovered that the level of the TRF2 protein, a key telomere-capping protein, declines in human skeletal muscle over lifetime. In cultured human myotubes, TRF2 downregulation did not trigger telomere dysfunction, but suppressed expression of the mitochondrial Sirtuin 3 gene (SIRT3) leading to mitochondrial respiration dysfunction and increased levels of reactive oxygen species. Importantly, restoring the Sirt3 level in TRF2-compromised myotubes fully rescued mitochondrial functions. Finally, targeted ablation of the Terf2 gene in mouse skeletal muscle leads to mitochondrial dysfunction and sirt3 downregulation similarly to those of TRF2-compromised human myotubes. Altogether, these results reveal a TRF2-SIRT3 axis controlling muscle mitochondrial function. We propose that this axis connects developmentally regulated telomere changes to muscle redox metabolism.