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.

中文翻译：

---

在整个生命周期中，骨骼肌纤维的线粒体功能受TRF2-SIRT3轴控制。

端粒的缩短遵循发育调节的过程，该过程导致分裂细胞的复制衰老。然而，端粒的变化是否参与有丝分裂后细胞功能和衰老仍然不清楚。在这项研究中，我们发现TRF2蛋白（一种关键的端粒封闭蛋白）的水平在人的骨骼肌中会持续下降。在培养的人肌管中，TRF2的下调不会触发端粒功能障碍，但会抑制线粒体Sirtuin 3基因（SIRT3）的表达，从而导致线粒体呼吸功能障碍和活性氧水平升高。重要的是，在TRF2受损的肌管中恢复Sirt3水平可完全挽救线粒体功能。最后，有针对性地切除Terf2小鼠骨骼肌中的该基因导致线粒体功能障碍和sirt3下调，与TRF2受损的人类肌管相似。总而言之，这些结果揭示了控制肌肉线粒体功能的TRF2-SIRT3轴。我们建议该轴将发育调节的端粒变化与肌肉氧化还原代谢联系起来。