Mitochondrial function in skeletal myofibers is controlled by a TRF2‐SIRT3 axis over lifetime

Abstract

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.

Role of Histone Deacetylases in Skeletal Muscle Physiology and Systemic Energy Homeostasis: Implications for Metabolic Diseases and Therapy

“…Interestingly, SIRT3 liver-specific knockout (hep −/− ) and skeletal muscle-specific knockout (skm −/− ) mice did not affect glucose homeostasis under chow or HFD conditions (Fernandez-Marcos et al, 2012). The above results indicate that SIRT3 has an important role in metabolic regulation, but in specific physiological processes such as redox state, exercise, and aging, and its regulatory mechanism is yet defined in skeletal muscles (Kong et al, 2010;Robin et al, 2020;Williams et al, 2020). A recent study found that SIRT4 knockout can resist HFD-induced obesity and increase endurance exercise in mice by repressing malonyl CoA decarboxylase, which was a key enzyme controlling fatty acid beta-oxidation and was reported to regulate muscle fuel switching between carbohydrates and fatty acids (Koves et al, 2008;Laurent et al, 2013).…”

Cellular aging beyond cellular senescence: Markers of senescence prior to cell cycle arrest in vitro and in vivo

“…With gradually decreasing telomere length, TRF2 increases its occupancy on non-telomeric chromatin regions, where it regulates epigenetic modifications and transcription (Mukherjee et al, 2018). In addition, the extratelomeric activity of TRF2 has been shown to contribute to angiogenesis (El Mai et al, 2014;Zizza et al, 2019) and mitochondria function in muscle (Robin et al, 2020). Similarly to Rap1, TRF2 translocates from telomeres to non-telomeric chromatin upon DNA damage (Bradshaw et al, 2005) and in senescence (Mitchell & Zhu, 2014).…”

The Power of Stress: The Telo-Hormesis Hypothesis

“…A similar TPE is conserved in Drosophila , mammals and Trypanosoma [ 135 , 136 , 137 , 138 , 139 , 140 , 141 ]. As in yeast, human TPE is regulated by long-range chromatin loops whose formation depends upon TL and shelterin subunits [ 142 , 143 , 144 , 145 ]. The existence of long-range chromatin-loops has first been described in yeast [ 146 , 147 , 148 , 149 , 150 ], then in plant [ 151 ] and in mammalian cells [ 146 , 147 , 149 , 152 , 153 ].…”

“…The existence of long-range chromatin-loops has first been described in yeast [ 146 , 147 , 148 , 149 , 150 ], then in plant [ 151 ] and in mammalian cells [ 146 , 147 , 149 , 152 , 153 ]. Although the mechanisms allowing these long-range interactions remain elusive, it has been shown that human telomeres can interact with interstitial telomeric sequences, or ITS, in a Lamin A/C and TRF2 dependent manner [ 145 , 154 ]. This chromatin looping is expected to have a direct impact on the transcriptional regulation of the associated subtelomeric genes [ 132 ].…”

“…Additionally, in human and mouse skeletal muscle, the expression of the mitochondrial sirtuin SIRT3 , a subtelomeric gene, is activated by TRF2 fixation at its locus through a long-distance chromatin loop. SIRT3 is downregulated upon TRF2 inhibition, leading to mitochondrial dysfunction, characterized by higher mitochondrial DNA content and ROS levels [ 145 ]. TRF2 downregulation in skeletal muscle occurs naturally during young adulthood.…”