Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production
ABSTRACT Reactive oxygen species (ROS), especially mitochondrial ROS, are postulated to play a significant role in muscle atrophy. We report a dramatic increase in mitochondrial ROS generation in three conditions associated with muscle atrophy: in aging, in mice lacking CuZn-SOD (Sod1(-/-)), and in the neurodegenerative disease, amyotrophic lateral sclerosis (ALS). ROS generation in muscle mitochondria is nearly threefold higher in 28- to 32-mo-old than in 10-mo-old mice and is associated with a 30% loss in gastrocnemius mass. In Sod1(-/-) mice, muscle mitochondrial ROS production is increased >100% in 20-mo compared with 5-mo-old mice along with a >50% loss in muscle mass. ALS G93A mutant mice show a 75% loss of muscle mass during disease progression and up to 12-fold higher muscle mitochondrial ROS generation. In a second ALS mutant model, H46RH48Q mice, ROS production is approximately fourfold higher than in control mice and is associated with a less dramatic loss (30%) in muscle mass. Thus ROS production is strongly correlated with the extent of muscle atrophy in these models. Because each of the models of muscle atrophy studied are associated to some degree with a loss of innervation, we were interested in determining whether denervation plays a role in ROS generation in muscle mitochondria isolated from hindlimb muscle following surgical sciatic nerve transection. Seven days post-denervation, muscle mitochondrial ROS production increased nearly 30-fold. We conclude that enhanced generation of mitochondrial ROS may be a common factor in the mechanism underlying denervation-induced atrophy.
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- "It has also been shown that oxidative stress levels correlate strongly with the extent of muscle mass reduction, neuromuscular junction (NMJ) denervation, and muscle fiber type switching in Sod1 À /À , SOD1-G93A, and old wild-type mice. Those changes can be detected as early as 4–5 months of age in Sod1 À /À animals . "
ABSTRACT: Reactive oxygen species (ROS) are believed to be important mediators of muscle atrophy and weakness in aging and many degenerative conditions. However, the mechanisms and physiological processes specifically affected by elevated ROS in neuromuscular units that contribute to muscle weakness during aging are not well defined. Here we investigate the effects of chronic oxidative stress on neurotransmission and excitation-contraction (EC) coupling mechanisms in the levator auris longus (LAL) muscle from young (4-8 months) and old (22-28 months) wild type mice and young adult Sod1(-/-) mice. The frequency of spontaneous neurotransmitter release and the amplitude of evoked neurotransmitter release in young Sod1(-/-) and old wild type LAL neuromuscular junctions were significantly reduced from the young wild type values, and those declines were mirrored by decreases in synaptic vesicle pool size. Presynaptic cytosolic calcium concentration and mitochondrial calcium uptake amplitudes showed substantial increases in stimulated young Sod1(-/-) and old axon terminals. Surprisingly, LAL muscle fibers from old mice showed a greater excitability than fibers from either young wild type or young Sod1(-/-) LAL muscle fibers. Both evoked excitatory junction potential (EJP) and spontaneous mini EJP amplitudes were considerably higher in LAL muscles from old mice than in fibers from young Sod1(-/-) LAL muscle. Despite a greater excitability, sarcoplasmic calcium influx in both old wild type and young Sod1(-/-) LAL muscle fibers was significantly smaller. Sarcoplasmic reticulum calcium levels were also smaller in both mice, but the difference was not statistically significant in muscle fibers from old wild type mice. The protein ratio of triad calcium channels - RyR1/DHPR was not different in all groups. However, fibers from both Sod1(-/-) and old mice had substantially elevated levels of protein carbonylation and S-nitrosylation modifications. Overall, our results suggest that young Sod1(-/-) recapitulate many neuromuscular and muscle fiber changes seen in old mice. We also conclude that muscle weakness in old mice might in part be driven by ROS mediated EC uncoupling, while both EC uncoupling and reduced neurotransmitter release contribute to muscle weakness in Sod1(-/-) mice. Copyright © 2015. Published by Elsevier Inc.Free Radical Biology and Medicine 04/2015; 84. DOI:10.1016/j.freeradbiomed.2015.03.021 · 5.74 Impact Factor
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- "Of note, the Sod1−/− fibroblasts exhibited a loss of mitochondrial membrane potential and enhanced mitochondria ROS generation. Likewise, Muller et al. reported that Sod1−/− skeletal muscle showed significant alterations in mitochondrial function, including increased mitochondrial ROS generation and reduced ATP production . Han et al. also revealed significantly higher levels of p53 and phospho-p53 in nuclei isolated from Sod1−/− livers . "
ABSTRACT: Aging is characterized by increased oxidative stress, chronic inflammation, and organ dysfunction, which occur in a progressive and irreversible manner. Superoxide dismutase (SOD) serves as a major antioxidant and neutralizes superoxide radicals throughout the body. In vivo studies have demonstrated that copper/zinc superoxide dismutase-deficient (Sod1(-/-) ) mice show various aging-like pathologies, accompanied by augmentation of oxidative damage in organs. We found that antioxidant treatment significantly attenuated the age-related tissue changes and oxidative damage-associated p53 upregulation in Sod1(-/-) mice. This review will focus on various age-related pathologies caused by the loss of Sod1 and will discuss the molecular mechanisms underlying the pathogenesis in Sod1(-/-) mice.BioMed Research International 09/2014; 2014:140165. DOI:10.1155/2014/140165 · 2.71 Impact Factor
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- "However, the neuromuscular sarcopenic phenotypes exhibited by this mouse share several characteristics with age-related sarcopenia, namely shift from fast to slow fiber type, mitochondrial dysfunction, and increased mitochondrial ROS generation (Jang and Van Remmen, 2009, 2011). In particular, the mitochondrial dysfunction might contribute to early motor terminal death in these mice (Muller et al., 2007). Rocha et al. (2013) have shown that the Sod1-/- mice undergo cycles of denervation/re-innervation by mixed NMJ populations (Sod1a, Sod1b) supporting morphological evidence for two populations of motor units in Sod1-/- mice (Schaefer et al., 2005). "
ABSTRACT: Aging is associated with a progressive loss of muscle mass and strength and a decline in neurophysiological functions. Age-related neuromuscular junction (NMJ) plays a key role in musculoskeletal impairment that occurs with aging. However, whether changes in the NMJ precede or follow the decline of muscle mass and strength remains unresolved. Many factors such as mitochondrial dysfunction, oxidative stress, inflammation, changes in the innervation of muscle fibers, and mechanical properties of the motor units probably perform an important role in NMJ degeneration and muscle mass and strength decline in late life. This review addresses the primary events that might lead to NMJ dysfunction with aging, including studies on biomarkers, signaling pathways, and animal models. Interventions such as caloric restriction and exercise may positively affect the NMJ through this mechanism and attenuate the age-related progressive impairment in motor function.Frontiers in Aging Neuroscience 08/2014; 6:208. DOI:10.3389/fnagi.2014.00208 · 4.00 Impact Factor