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.
Highlights
Sarcopenia is an advanced age-related loss of skeletal muscle and function, which reduces the amount of metabolically active tissue, increasing the risk for metabolic diseases [1, 2], and negatively impacts mobility, limiting the independence living and quality of life of elderly individuals [3, 4]
poly(ADP-ribose) polymerases (PARPs)-1 activity can be modulated by its acetylation level [37, 39], and we explored the acetylation of PARP-1, as a potential mechanism that would explain the decline in PARP-1 activity in skeletal muscle from young mice
Concomitant with the decreased association of GCN5 with PARP-1, the level of GCN5 protein was significantly lower in exercisedskeletal muscle (Fig. 1J). These results indicate that the potential mechanism whereby Silent information regulator 1 (SIRT-1) protects skeletal muscle in young mice from the elevated PARP-1 activity that is seen in old age, is via increased deacetylation-dependent inactivation and/or reduced GCN5 levels in response to exercise
Summary
Sarcopenia is an advanced age-related loss of skeletal muscle and function, which reduces the amount of metabolically active tissue, increasing the risk for metabolic diseases [1, 2], and negatively impacts mobility, limiting the independence living and quality of life of elderly individuals [3, 4]. AGING, October 2014, Vol 6 No. sarcopenia by controlling many cellular pathways including redox-sensitive signaling pathways [11]. The mitochondria are both ROS producers and are adversely affected by excessive ROS levels. A comparative electron-microscopic study of the ultrastructure of mitochondria in skeletal muscles of young (low basal ROS levels) and old rats (high basal levels of ROS) revealed age-dependent changes in both the general organization of the mitochondrial reticulum and the ultrastructure of mitochondria [12], which presumably contributes to the age-associated dysfunction of this organelle. Early treatment of aged mice with the mitochondrial antioxidant SkQ1 was shown to prevent the development of age-dependent destructive pathological changes in mitochondria [12]
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