Age, Injury, and the Neuromuscular Junction

Abstract This application for an Independent Scientist Award (K02) is designed to advance knowledge important for understanding mechanisms of age-related changes at the NMJ and support the career of Dr. Sarah M. Greising, PhD, an Associate Professor in the School of Kinesiology at the University of Minnesota. As the elderly population of the United States continues to increase there is an ongoing scientific necessity to understand the causes of neuromuscular dysfunction in old age. Understanding neuromuscular dysfunction requires fundamental evaluations of the neuromuscular junction (NMJ) the point of contact between a motor neuron and skeletal muscle fiber. The NMJ initiates muscle contraction and allows physical movement including the ability to breathe across the lifespan. Without innervation, muscle fibers cannot contract, significantly reducing function. The overall objective of this K02 application is to characterize and correct neuromuscular deficiency and low plasticity in the skeletal muscle following both aging and injury by evaluating if shared mechanisms of destabilization of the NMJ exist. This proposal will capitalize on two pathologies that have limited regenerative potential of skeletal muscle by evaluating the NMJ across the aging trajectory of mid- to old-age and following volumetric muscle loss (VML), which is clinically identified as a chronic and irrecoverable loss of skeletal muscle tissue resulting in functional impairments. Both aging and VML injury result in considerable neuromuscular dysfunction, and chronic co-morbidities. My central hypothesis is that progressive NMJ destabilization in aged and injured skeletal muscle create a hostile cellular environment in the muscle that mitigates plasticity and blunts the effectiveness of interventions. I propose two specific aims to address these hypotheses: 1) To understand the limits of diminished innervation and NMJ destabilization; and 2) To determine what spatial changes occur at the NMJ during progressive destabilization. The results of the proposed studies will define cellular mechanisms that contribute to the finite adaptive and regenerative capacity of the remaining muscle after injury and aging and how this relates to NMJ destabilization. The stated goal of the K02 award is to foster the development of outstanding scientists and enable them to expand their potential to make significant contributions to their field of research. This K02 award will advance and reinvigorate Dr. Greising’s scientific development in aging biology by providing protected time to: 1) to build preliminary data and a conceptual framework for a competitive NIA R01-level grant proposal, 2) evaluate mechanisms of NMJ dysregulation in aged and injured skeletal muscle, and 3) build my education and understanding of omics-based tools to develop collaborations able to ask and answer impactful questions linking the physiology of the NMJ (my expertise) and these novel techniques (collaborative expertise).