Mitochondrial ROS Amplify Nox2 Signaling and Atrophy in the Rat Soleus with 7 Days of Hindlimb Unloading (LB821)

Abstract

Removal of mechanical loading during spaceflight, bedrest, or immobilization causes rapid and profound atrophy of skeletal muscle. Emerging data suggest that oxidative stress from mitochondrial sources may contribute to unloading‐induced skeletal muscle atrophy. We recently found that the Nox2 isoform of NADPH oxidase is also upregulated in the unloaded soleus muscle, associated with FoxO3a activation and fiber atrophy. We used a mitochondrial specific antioxidant peptide (SS‐31) to test the hypothesis that mitochondrial ROS are involved in feed‐forward or amplification signaling with Nox2 in response to mechanical unloading of the rat soleus muscle. F344 rats were divided (n=7/grp) into the following groups: ambulatory control (CON), ambulatory + SS‐31 (1.5 mg/kg/d) (AS), hindlimb unloaded for 7 days (HU), and HU + SS‐31 (HUS). SS‐31 significantly attenuated the reduction in soleus mass and soleus mass/body mass ratio elicited by HU. SS‐31 also abrogated an increase in Type II fibers during unloading. In addition, SS‐31 significantly blunted upregulation of Nox2 subunit p67phox in the unloaded soleus, using fluorescent signal intensity and p67phox membrane localization as markers. Our results are consistent with the postulate that mechanical unloading of skeletal muscle causes mitochondrial ROS to upregulate Nox2 and thus drive atrophy and fiber‐type shift from slow to fast. Supported by NASA (NNX13AE45G), NIH (AR054084), and the Huffines Institute.Grant Funding Source: NASA