Increased superoxide in vivo accelerates age‐associated muscle atrophy through mitochondrial dysfunction and neuromuscular junction degeneration

Abstract

Oxidative stress has been implicated in the etiology of age-related muscle loss (sarcopenia). However, the underlying mechanisms by which oxidative stress contributes to sarcopenia have not been thoroughly investigated. To directly examine the role of chronic oxidative stress in vivo, we used a mouse model that lacks the antioxidant enzyme CuZnSOD (Sod1). Sod1(-/-) mice are characterized by high levels of oxidative damage and an acceleration of sarcopenia. In the present study, we demonstrate that muscle atrophy in Sod1(-/-) mice is accompanied by a progressive decline in mitochondrial bioenergetic function and an elevation of mitochondrial generation of reactive oxygen species. In addition, Sod1(-/-) muscle exhibits a more rapid induction of mitochondrial-mediated apoptosis and loss of myonuclei. Furthermore, aged Sod1(-/-) mice show a striking increase in muscle mitochondrial content near the neuromuscular junctions (NMJs). Despite the increase in content, the function of mitochondria is significantly impaired, with increased denervated NMJs and fragmentation of acetylcholine receptors. As a consequence, contractile force in aged Sod1(-/-) muscles is greatly diminished. Collectively, we show that Sod1(-/-) mice display characteristics of normal aging muscle in an accelerated manner and propose that the superoxide-induced NMJ degeneration and mitochondrial dysfunction are potential mechanisms of sarcopenia.

Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue

“…These observed changes have earlier been described in old rodents (Usuki et al, 2004) and human muscle (Larsson, 1978). However, we cannot exclude that disruption of the neuromuscular junction may have some influence on the observed motor phenotype of the mutant mice as previously published in mice deficient for the Cu, Zn superoxide dismutase (Jang et al, 2010). Serial sections of the spinal cord with a-motor neurons and neurons from the cerebral cortex did not reveal any morphological changes (data not shown).…”

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

“…Oxidative stress has been proposed to play an important role in the initiation and progression of muscle atrophy during aging (Muller et al ., 2006; Jang et al ., 2010). Previous studies have reported elevated antioxidant enzyme activity from treatment with butyrate and HDAC inhibitors (Kang et al ., 2002; Shimazu et al ., 2013).…”

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

“…Thus, the neuromuscular ageing phenotype observed in the SOD1 −/− model is likely associated with disrupted redox signalling within both the cytosolic and mitochondrial subcellular compartments. Elevated levels of oxidative damage and atrophy shown in skeletal muscle of SOD1 −/− are accompanied by increased mitochondrial generation of reactive species, impaired mitochondrial bioenergetic function and mitochondrial release of proapoptotic factors, which ultimately lead to apoptotic loss of myonuclei 276. These findings imply that the mitochondrial redox environment plays a central role in regulating skeletal muscle mitochondrial function.…”

“…Increased oxidative damage and compensatory up‐regulation of redox regulatory enzymes, stress responses and adaptive signalling pathways observed in muscle from SOD1 −/− mice30, 33 were not present in the neuron‐specific transgenic SynTgSOD1 −/− model. Moreover, the accelerated degeneration in NMJ structure, including both presynaptic and postsynaptic NMJ features,23, 276 failure of neuromuscular transmission29, 278 and impaired in situ muscle‐force generation34, 277 that occur in the whole body SOD1 −/− model were completely rescued in the nerve rescue model 29…”