PROJECT 1: Contribution of altered synapse function to muscle atrophy and weakness in aging

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ABSTRACT – PROJECT 1 With aging, skeletal muscle displays atrophy and weakness that limits mobility, contributes to disability, and reduces quality of life. Strong associations are reported between declines with aging in muscle structure and function and degenerative changes in the morphology of neuromuscular junctions (NMJ); however, events with aging that trigger disruption of NMJs and the downstream mechanisms of impaired muscle function and fiber loss are all unknown. Studies from our groups collectively show a recapitulation, in an accelerated fashion, of key attributes of muscle aging in mice deficient in copper zinc superoxide dismutase (CuZnSOD; Sod1KO mice). Additional studies using novel mouse models we developed with tissue specific modulation of Sod1 collectively suggest that redox homeostasis in motor neurons is a critical factor regulating the maintenance of NMJs, but that the progression of sarcopenia is determined by interactions between changes in both neurons and muscle. The goal of Project 1 is to establish mechanisms by which alterations in motor neuron redox homeostasis cause post-synaptic changes in muscle. Increased production of reactive oxygen species (ROS) by muscle mitochondria is a hallmark of manipulations that cause NMJ degeneration and muscle atrophy, e.g. Sod1 deficiency, aging, and denervation. Thus, our hypothesis is that with aging, altered redox homeostasis in peripheral motor neurons impairs NMJ formation and maintenance during synaptic turnover and the resultant disruption in innervation alters muscle mitochondrial function that causes increased oxidative damage to the muscle activation and contractile machinery. We will test this hypothesis by determining the impact of oxidative stress in motor neurons on NMJ formation and maintenance and the impact of directly disrupting NMJs on key postsynaptic muscle functions. Oxidative stress and NMJ disruption will be induced using novel tissue-specific mouse models provided by the Animal Core. These powerful new mouse models coupled with innovative methods for studying NMJ formation and regeneration, mitochondrial function, calcium homeostasis, and force generation, provide a potent paradigm for impacting scientific knowledge of skeletal muscle aging to drive successful interventions to prevent sarcopenia.