Dysregulation of SIRT-1 in aging mice increases skeletal muscle fatigue by a PARP-1-dependent mechanism

Abstract

Accumulation of reactive oxygen species (ROS) in skeletal muscles and the resulting decline in muscle performance are hallmarks of sarcopenia. However, the precise mechanism by which ROS results in a decline in muscle performance is unclear. We demonstrate that isometric-exercise concomitantly increases the activities of Silent information regulator 1 (SIRT-1) and Poly [ADP-ribose] polymerase (PARP-1), and that activated SIRT-1 physically binds with and inhibits PARP-1 activity by a deacetylation dependent mechanism in skeletal muscle from young mice. In contrast, skeletal muscle from aged mice displays higher PARP-1 activity and lower SIRT-1 activity due to decreased intracellular NAD+ content, and as a result reduced muscle performance in response to exercise. Interestingly, injection of PJ34, a PARP-1 inhibitor, in aged mice increased SIRT-1 activity by preserving intracellular NAD+ content, which resulted in higher skeletal muscle mitochondrial biogenesis and performance. We found that the higher activity of PARP-1 in H2O2-treated myotubes or in exercised-skeletal muscles from aged mice is due to an elevated level of PARP-1 acetylation by the histone acetyltransferase General control of amino acid synthesis protein 5-like 2 (GCN-5). These results suggest that activation of SIRT-1 and/or inhibition of PARP-1 may ameliorate skeletal muscle performance in pathophysiological conditions such as sarcopenia and disuse-induced atrophy in aging.

NAD and the aging process: Role in life, death and everything in between

“…In particular, at the same time that PARPs appear to have a beneficial effect on the control of DNA integrity and may positively contribute to an increase in organismal longevity, its over-activation during the aging process may contribute to cellular NAD decline and metabolic dysfunction (Figure 4). Interestingly, this appears to be the case, since it was proposed that over-activation of PARP1 in skeletal muscle of old mice during exercise can lead to cellular NAD decline that may contribute to exercise-induced fatigue and reduced muscle performance in response to exercise during aging (Mohamed et al, 2014). …”

Mitochondria Initiate and Regulate Sarcopenia

“…This includes identifying the mitochondrial modifications that are reversible by exercise and nutritional interventions in aging. For example, mitochondrial acetylation is reversible at least under some circumstances including exercise (97). Proteins like SIRT1 and SIRT3 may be important regulators of deacetylation in mitochondria (46, 97, 132).…”

“…For example, mitochondrial acetylation is reversible at least under some circumstances including exercise (97). Proteins like SIRT1 and SIRT3 may be important regulators of deacetylation in mitochondria (46, 97, 132). SIRT1 is important for deacetylation of mitochondrial-interacting targets like PGC-1α, FOXO3, p53 and NF-kB (Reviewed in (13, 110) and has been implicated in improving function and life span in aging (95).…”

Frailty and sarcopenia as the basis for the phenotypic manifestation of chronic diseases in older adults

“…Reduced skeletal muscle performance in response to exercise in aged mice is associated with lower activity of SIRT1 in this tissue, which is in turn related to an increase in poly (ADP-ribose) polymerase (PARP-1) activity that diminishes intracellular NAD levels. Increment of SIRT1 activity by PARP-1 inhibition results in higher skeletal muscle mitochondrial biogenesis and performance (Mohamed et al, 2014). Moreover, SIRT1 activity up-regulation is likely involved in the protective effects of exercise training on aged skeletal muscle in rats (Koltai et al, 2010).…”