The role of telomere damage in cardiomyocyte ageing

Abstract

Cellular senescence is often defined as an irreversible cell cycle arrest of mitotic cells, however post-mitotic cells, including adipocytes and neurones, have also been shown to display senescent-like characteristics, such as elevated SA-β-Gal activity and increased production of pro-inflammatory cytokines, in response to persistent DNA damage. Our group have shown that a persistent DDR can occur at telomeres independently of length. We investigated the possibility of telomere dysfunction being associated with senescence in a non-rapidly dividing cell type, which is not subject to repeated end-replication problem-associated telomere shortening. We show that telomere damage can be induced in cardiomyocyte cell lines with X-irradiation or oxidative stress in the absence of cell division, with live-cell imaging revealing the presence of persistent DNA damage foci. Endonuclease-mediated telomere-specific double-strand DNA breaks trigger a senescent-like phenotype in cardiomyocytes in vitro, including elevated SA-β-Gal activity, p21 expression, hypertrophy and decrease of proliferation marker Ki-67. We observed an age-dependent increase in telomere dysfunction in both murine and human cardiomyocytes, occurring independently of telomere length. Furthermore, murine cardiomyocytes in vivo are associated with numerous markers of senescence, such as p15, p16 and p21 elevation, along with increased TGF-β expression and increased prevalence of senescence-associated distension of satellites. Increased oxidative stress via MnSOD-/+, Catalase-/-, or MAO-A overexpression (resulting in excess H2O2 production), can drive telomere dysfunction in murine cardiomyocytes in vivo, which correlates with a decrease in heart function, both of which can be rescued with anti-oxidant supplementation. Finally, we show that rapamycin, a drug shown to increase lifespan and delay age-related diseases in numerous organisms, can attenuate the accumulation of TAF in murine cardiomyocytes in vivo, and is associated with a decrease in senescence markers. Our data provide evidence that telomere dysfunction occurs independently of length in cardiomyocytes, and is associated with a senescent-like phenotype.