Adaptive plasticity of autophagic proteins to denervation in aging skeletal muscle

Abstract

Aging muscle exhibits a progressive decline in mass and strength, known as sarcopenia, and a decrease in the adaptive response to contractile activity. The molecular mechanisms mediating this reduced plasticity have yet to be elucidated. The purposes of this study were 1) to determine whether denervation-induced muscle disuse would increase the expression of autophagy genes and 2) to examine whether selective autophagy pathways (mitophagy) are altered in aged animals. Denervation reduced muscle mass in young and aged animals by 24 and 16%, respectively. Moreover, young animals showed a 50% decrease in mitochondrial content following denervation, an adaptation that was not matched by aged animals. Basal autophagy protein expression was higher in aged animals, whereas young animals exhibited a greater induction of autophagy proteins following denervation. Localization of LC3II, Parkin, and p62 was significantly increased in the mitochondrial fraction of young and aged animals following denervation. Moreover, the unfolded protein response marker CHOP and the mitochondrial dynamics protein Fis1 were increased by 17-and 2.5-fold, respectively, in aged animals. Lipofuscin granules within lysosomes were evident with aging and denervation. Thus reductions in the adaptive plasticity of aged muscle are associated with decreases in disuse-induced autophagy. These data indicate that the expression of autophagy proteins and their localization to mitochondria are not decreased in aged muscle; however, the induction of autophagy in response to disuse, along with downstream events such as lysosome function, is impaired. This may contribute to an accumulation of dysfunctional mitochondria in aged muscle. reactive oxygen species; muscle atrophy; mitochondria; mitophagy; apoptosis SKELETAL MUSCLE IS A REMARKABLY plastic tissue that undergoes a striking transformation in response to decreases in contractile activity. This distinctive response is attributable to the multinucleated composition of muscle fibers and the coordinated activation of several catabolic signaling pathways. Although muscle retains its adaptability throughout the life of an organism, tissue malleability is reduced with advancing age (4, 22). Aged muscle is further affected by an age-associated loss of skeletal muscle mass and strength, a condition known as sarcopenia (8,22,42). Although the precise cellular mechanisms responsible for mediating sarcopenia have yet to be fully elucidated, several studies have implicated decreases in mitochondrial function and a corresponding increase in mitochondrially mediated cell death (apoptosis) as factors contributing to this age-induced decline (4, 8). Indeed, mitochondrially mediated apoptosis can be activated by increases in reactive oxygen species (ROS), which have also been associated with several other deleterious effects, including the oxidation of mitochondrial DNA, lipids, and proteins (10, 39). Our laboratory has shown that mitochondria from aged muscle generate more ROS, possess a lower mitochondrial membrane pot...

Epigallocatechin-3-gallate improves plantaris muscle recovery after disuse in aged rats

“…We have assumed that adding new nuclei are an important component in determining the regeneration potential of muscle after disuse, however, it is not clear how tightly regulated the nuclear/cytoplasmic domain is to regain loss muscle back to basal levels (which might be different than purely inducing hypertrophy over basal levels). We did not determine if autophagy or proteolytic changes also occurred in response to EGCg in old rat muscles in response to reloading after disuse, but this would be interesting given the observation that there is a suppressed level of autophagic signaling in muscles of aged rodents (Wohlgemuth et al, 2010) and in aged muscles under conditions of denervation-induced disuse (O’Leary et al, 2013). …”

Mitochondria Initiate and Regulate Sarcopenia

“…Contrary data suggest that mitophagy may be increased in aging muscles as evidenced by greater migration of Parkin and p62 to the mitochondria (103). Nevertheless, an accumulation of lipofuscin granules suggests a failure of the lysosome to remove dysfunctional mitochondrial in aging even when Parkin has translocated to the mitochondria (103).…”

“…Nevertheless, an accumulation of lipofuscin granules suggests a failure of the lysosome to remove dysfunctional mitochondrial in aging even when Parkin has translocated to the mitochondria (103). Indeed, lipofuscin deposits have been reported previously in many tissues including muscles and neurons of aged rodents or other mammals (138).…”

Mitochondria, Muscle Health, and Exercise with Advancing Age

“…A recent study from our laboratory documented an increase in the localization of Parkin and p62 to the mitochondria, suggestive of an increase in mitophagy with age (119). However, also evident was a marked accumulation of lipofuscin granules, suggestive of lysosomal dysfunction (119). This could directly impact the removal of mitochondria in aged muscle by preventing the fusion of the autophagosome with the lysosome (FIGURE 3).…”