Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production

Abstract

Van Remmen H. Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production. Am J Physiol Regul Integr Comp Physiol 293: R1159-R1168, 2007. First published June 20, 2007; doi:10.1152/ajpregu.00767.2006.-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 Ϫ/Ϫ ), 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 Ϫ/Ϫ mice, muscle mitochondrial ROS production is increased Ͼ100% in 20-mo compared with 5-mo-old mice along with a Ͼ50% 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 postdenervation, 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. mitochondria; reactive oxygen species; amyotrophic lateral sclerosis; copper, zinc superoxide dismutase SKELETAL MUSCLE ATROPHY is a debilitating phenotype that is associated with a variety of conditions, including neurodegenerative diseases, cancer cachexia, and immobilization or disuse (49,56,76,77). Muscle atrophy is also an unavoidable consequence of normal human aging (43, 68). Despite the importance and impact of losing muscle mass, the biochemical and molecular mechanisms leading to muscle atrophy are still poorly understood. Several potential contributing factors in loss of muscle mass have been identified, including neuromuscular alterations, changes in protein synthesis and degradation, and loss of fibers due to apoptosis (15,52,58). Oxidative stress and mitochondrial dysfunction have also been implicated in sarcopenia (27, 62), hindlimb unloading (3, 46, 65), and in atrophic mouse muscle from amyotrophic lateral sclerosis (ALS) transgenic mice (54). Because mitochondria are an important source of reactive oxygen species (ROS) in cells, we were interested in delineating the role of muscle mitochondrial ROS generation in muscle atrophy. In this study, we measured mitochondrial ROS prod...

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