The biochemical and molecular mechanisms responsible for the loss of muscle mass during aging are not well understood. We have previously reported that mice lacking CuZn-superoxide dismutase (Sod1-/- mice) have high levels of superoxide-induced oxidative stress and exhibit an accelerated, age-related loss of muscle mass associated with alterations in skeletal muscle mitochondrial function. These mice are a valuable tool that will allow us test the hypothesis that superoxide-induced oxidative stress initiates a loss of muscle fiber innervation, muscle mitochondrial dysfunction, elevated production of ROS and mitochondria release of apoptotic factors that contribute to muscle atrophy. We will use tissue specific rescue of CuZnSOD activity in Sod1-/- mice to directly determine the role of superoxide-induced oxidative stress in neurons (Sod1-/- (N+) mice) and skeletal muscle (Sod1-/- (M+) mice) on alterations in muscle mitochondrial function and age related loss of muscle mass. First, we will test the hypothesis that oxidative stress-induced loss of innervation in the neuron is the initiating event leading to mitochondrial dysfunction in the Sod1-/- mice by comparing muscle mitochondrial function and muscle atrophy in wild type (WT), Sod1-/-, Sod1-/- (N+) and Sod I-/- (M+) mice as a function of age. Using these mouse models, we will also investigate the mechanism by which superoxide-induced oxidative stress leads to muscle mitochondrial dysfunction. We propose that superoxide induced oxidative stress and damage in the neurons initiates alterations in muscle mitochondrial function through a mechanism that involves changes in phospholipase A2 (PLA2) activity, alterations in lipid composition of the mitochondrial membrane and compromised activities of electron transport complex in muscle mitochondria. Finally, we will determine the effect of altered mitochondrial function on mitochondrial apoptotic signaling and loss of muscle mass. We propose that alterations in mitochondrial function in muscle of the Sod1-/- mice contribute to loss of muscle mass through increased release of apoptotic factors (e.g., AIF, Cytc, Smac/Diablo, HtrA2/Omi, Endonuclease G). To test this we will measure the release of apoptotic factors from skeletal muscle mitochondria isolated from Sod1-/-, Sod1-/- (N+) and Sod1-/-(M+) mice and determine whether apoptotic signaling is activated, leading to atrophy of muscle fibers.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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University of Michigan Ann Arbor
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