OVERALL ABSTRACT. The goal of this Program Project (P01) Grant is to provide much needed information regarding the mechanisms underlying age-associated loss of skeletal muscle mass and strength, often referred to as sarcopenia. Studies from our team show that mice deficient in copper zinc superoxide dismutase (CuZnSOD, Sod1KO mice) display progressive declines in muscle structure and function throughout early adulthood, such that by middle age the Sod1KO mice resemble very old wild type mice. These findings support a mechanistic link between chronic oxidative stress and sarcopenia. A key feature of the initiation of muscle declines with aging and in Sod1KO mice is the degeneration of neuromuscular junctions (NMJs). To probe the importance of pre- and post-synaptic factors in sarcopenia, we developed new mouse models with nerve- or muscle-specific deficiency of Sod1 or with Sod1 restored in neurons of Sod1KO mice. These mice have produced several key findings: 1-partial rescue of CuZnSOD only in neurons of Sod1KO mice prevented premature muscle atrophy, 2-deficiency of CuZnSOD only in neurons caused less severe atrophy than is observed in Sod1KO mice, and 3-lack of CuZnSOD only in muscle resulted in weakness without atrophy. These data indicate that motor neuron deficits arising from an oxidized redox status are critical in sarcopenia, but reduction of Sod1 in either neurons or skeletal muscle alone does not replicate the phenotype of Sod1KO mice, suggesting an interactive effect between both muscle and neural tissues. Thus, our objective is to critically test this ?two-hit? mechanism for sarcopenia. We hypothesize that (1) defects in neuronal function arising from altered redox homeostasis, due to Sod1 deficiency or aging, initiate disruption of NMJs resulting in muscle mitochondrial dysfunction; and (2) under circumstances of impaired ability of muscles to maintain mitochondrial function, resultant changes in ROS, calcium, and/or inflammation will feed back to further impair maintenance of the NMJ. We will address this hypothesis in a set of highly integrated Aims that will determine 1. the impact of altered redox homeostasis in motor neurons on NMJ formation and function, 2. whether NMJ degeneration and increased ROS generation by muscle mitochondria (mtROS) are necessary to induce sarcopenia, and 3. the role of muscle mtROS, calcium, and inflammation in the weakness and muscle fiber loss. We will achieve these Aims through three synergistic Projects supported by Administrative and Animal Resource Cores that are key to the success of this interactive P01 that relies on shared animal models, frequent contact, and highly collaborative science.
Age-related declines in muscle mass and function are important contributors to the major public health problem of frailty, which causes the loss of mobility, independence, and quality of life among the elderly at an estimated financial cost of $90 billion per year. The mechanistic insights provided by this P01 will have a significant positive impact on knowledge across the entire aging neuromuscular system that could not be gained if Projects were pursued independently. The relevance lies in the increased understanding of the mechanisms underlying muscle loss and weakness that is critical for identifying targets for intervention with maximum effectiveness.
