Abstract
PURPOSE: Hind-limb immobilization (e.g. casting) in rodents results in significant atrophy in both the soleus and plantaris muscles. In this regard, oxidative stress has been proposed to play a major role in muscle fiber atrophy during periods of prolonged skeletal muscle inactivity. These experiments tested the hypothesis that hind-limb immobilization leads to increased mitochondrial ROS emission and mitochondrial bioenergetic dysfunction. We also hypothesized that the mitochondrial-targeted antioxidant SS31 can prevent immobilization-induced mitochondrial dysfunction and rescue the inactivity-induced loss of mass in the soleus and plantaris muscles. METHODS: C57/B16 mice were randomly assigned to one of three experimental groups: 1) ambulatory controls; 2) 14-days of hind-limb immobilization; and 4) 14-days of hind-limb immobilization and treated with the mitochondrial antioxidant, SS-31. At the completion of the experiments, the soleus, and plantaris weights were recorded and mitochondria function was determined by measuring state 3 and state 4 respiration rates. In addition, the levels of oxidatively modified muscle proteins were determined by 4-HNE. RESULTS: Compared to control, 14 days of hind-limb immobilization resulted in significant atrophy in both the soleus and plantaris muscles. Treatment with SS31 rescued this immobilization-induced decrease in the soleus and plantaris muscle weights. Further, hind-limb immobilization resulted in mitochondrial uncoupling and oxidative stress in both the soleus and plantaris muscles, but treatment of animals with SS31 prevented the inactivity-induced mitochondrial dysfunction and attenuated the increase in oxidative stress in both muscles. CONCLUSION: Collectively, these results support the hypothesis that mitochondrial ROS emission contributes to immobilization-induced skeletal muscle atrophy and that mitochondrial-targeted antioxidants prevent disuse-induced oxidative damage and atrophy in locomotor skeletal muscles. Supported by NIH R01 HL087839 awarded to SKP
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