NIH Grant P01 AG051442 titled ?Molecular Mechanisms of Neuromuscular Interactions Underlying Age-related Atrophy? Project Summary (Abstract) Physical frailty, with its associated immobility and disability, is a major factor limiting independence among the elderly. A foremost contributor to frailty is a decline in muscle mass and strength called sarcopenia. Loss of muscle in old age has been observed in every organism studied, yet despite its universality and personal and societal costs, a lack of understanding of the mechanism of sarcopenia remains a critical barrier to the development of effective interventions. Oxidative stress is proposed to play a key role in a variety of aging changes, including sarcopenia. We showed that mice deficient in the antioxidant enzyme copper zinc superoxide dismutase (CuZnSOD, Sod1KO) display elevated oxidative stress and a phenotype of accelerated neuromuscular aging. Essentially every attribute of normal neuromuscular aging is observed early in life in Sod1KO mice, including nerve conduction defects, degeneration of neuromuscular junctions (NMJ), increased production of reactive oxygen species by muscle mitochondria (mtROS), muscle weakness and fiber loss. The great extent to which neuromuscular changes in Sod1KO mice mimic those of normal aging indicates that Sod1KO mice provide an excellent model to study how oxidative stress causes sarcopenia and a unique system with which to gain mechanistic insight into age-related atrophy and weakness. The overall hypothesis of P01 AG051442 is 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 elevated muscle mtROS; and (2) under circumstances of impaired ability of muscle to maintain mitochondrial function, resultant changes in ROS, calcium, and/or inflammation will feed back to further impair maintenance of the NMJ. P01 investigators are examining each component of the hypothesis through a highly interactive set of studies testing the role of redox status in motor neurons in NMJ formation and maintenance (Project 1), the influence of pre-and post-synaptic events on loss of muscle mass and strength (Project 2), and the impact of aging and CuZnSOD deficiency on motor neuron and muscle redox status (Project 3). The focus of this application, submitted under PA-18-586 ?Research Supplements to Promote Diversity in Health-Related Research? is to support the career development of Dr. Lemuel Brown through studies of potential interactions between ROS and inflammation in NMJ and muscle regeneration and maintenance. Research and career development activities are proposed to expand his technical skill set, increase his knowledge of immunology, and provide opportunities for participation in professional activities to enhance his research potential and advance his ability to pursue an independent research career focused on inflammation as a contributor to age- associated muscle declines.
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.
