Sherif M Elbasiouny - US grants

ABSTRACT Forty-two percent of older adults have one or more physical limitations performing daily tasks that are essential for maintaining independence in the community. Age-related weakness is an important contributor to physical impairments, as weakness predisposes older adults to a 4-fold increase in physical limitations. For decades, age-related weakness was largely attributed to the loss of muscle mass, but recent data indicates that mass plays a lesser role than originally thought, highlighting that other neurological and/or muscle quality related factors are critical in the development of weakness. Despite the significance of maintaining physical strength in aging, the majority of the research has focused on maintaining muscle mass. Considerably less is known regarding the neural mechanisms potentially contributing to age-related weakness. This knowledge gap represents a barrier to the development of new interventions to enhance strength and function in older adults. In this application we will test the central hypothesis that age-related weakness is due, in part, to upregulation in motor neuron (MN) SK channels (small conductance calcium-activated potassium channels) that results in type- dependent reductions in intrinsic MN excitability and firing rates. Prior work indicates that aging results in reduced number of MUs (the ?-MN and the muscle fibers that it innervates) and lower firing rates. However, prior work has stopped short of determining whether age-related reductions in MU numbers are related to clinically- meaningful weakness, and determining the ionic mechanisms underlying reduced MN firing rates in aging. In this application we propose a series of parallel, cross-sectional and longitudinal animal (Aims 1 and 2) and human experiments (Aim 3) to test our central hypothesis. Aim 1 will determine if MN excitability dysfunction is involved in age-related weakness and determine its temporal relationship to MU loss in mice. Aim 2 will identify the cellular mechanisms underlying MN excitability dysfunction in aged mice. Aim 3 will determine the role of MN excitability and number in clinically-meaningful, age-related weakness in older adults. This work aligns with stated goals from the National Institute on Aging (NIA). The knowledge to be gained from this work has the potential to fundamentally shift the fields of sarcopenia and frailty research towards MN excitability as an early biomarker for the development of weakness, and identifying key MN ion channels that could serve as a neurotherapeutic targets for treating or preventing age-related weakness.