The Effect of Voluntary Wheel Running on Muscle Mass, Mitochondrial Function and Oxidative Damage in Sod1???/???mice

Abstract

An absence in a major antioxidant enzyme CuZnSOD (SOD1) leads to age-related muscle loss. Exercise training has been demonstrated to induce beneficial changes in both muscle mass and function. The aim of the present study was to examine the potential protective effect of long-term voluntary wheel running (VWR) on muscle mass, mitochondrial function (including ROS and ATP production, RCR), and, on oxidative damage markers (cytosolic protein carbonyls and tissue F2-isoprostanes) in old Sod1−/− mice (20 months of age). At three months of age, mice were randomly divided into four different groups: WT and Sod1−/− (sedentary), and, WT and Sod1−/− (VWR), for a period of 15 months. Sod1−/− mice ran approximately 30% less than WT mice on a daily average. VWR induced positive changes in muscle mass in all three muscles studied (soleus, tibialis anterior and gastrocnemius) for both Sod1−/− and WT. When normalized to body weight (muscle mass/body weight), VWR increased the ratio for all three muscles, in both WT and Sod1−/−mice. Mitochondrial ROS production was increased in untrained Sod1−/− when compared to WT, either during State 1 (no exogenously added substrate) or when using Complex I or II specific substrates (glutamate/malate or succinate+rotenone, respectively). However, in response to long term VWR mitochondrial ROS production was reduced in State1 and glutamate/malate supported respiration (but not with succinate+rotenone) for the Sod1−/− mice. These changes would suggest a beneficial effect on mitochondrial function, but ATP production rates and RCR (State 3/State4) were measured to be unchanged. VWR had no effect on oxidative damage to protein as measured by the levels of cytosolic protein carbonyls in WT animals, but resulted in an increase in this parameter in muscle from the Sod1−/− mice. Oxidative damage to lipids, as measured by the levels of F2-isoprostanes, was increased in muscle from Sod1−/− mice when compared to WT, regardless if trained or sedentary. VWR did not induce further increases in F2-isoprostane levels in any of the measured groups. Collectively, these data suggest that although VWR reduced ROS production by Sod1−/− mitochondria, elevated levels of oxidative damage may play a role in the discovered limitation in voluntary wheel running. Supported by NIH P01 AG20591 (H.V.R.), MDA Grant MDA3879 (H.V.R.), and ACSM(Texas) SRDA to YCJ