Project Summary Fatigue, lack of physical and/or mental energy, is a common reported symptom with osteoarthritis (OA) that may limit physical capacity and contribute to disability. In healthy older adults, muscle fatigue has been proposed as a key contributor to symptoms of fatigue. Knee extensor muscle dysfunction, including lower isometric and isokinetic torques and altered muscle activation patterns, are common with knee osteoarthritis (KOA). Together these changes in neuromuscular function may increase locomotor muscle fatigue in KOA compared to age-matched controls, as a greater percentage of the muscle’s capacity must be used for daily activities such as walking. To date, evidence to explain whether and how muscle fatigue may alter control and coordination of movement in KOA is limited. Our working hypothesis is that KOA-related neuromuscular changes may exacerbate locomotor muscle fatigue (Aim 1) and alter the neuro-mechanical response to muscle fatigue during gait (Aim 2), thereby contributing to mobility declines. In healthy adults, central and peripheral mechanisms can both contribute to muscle fatigue. However, whether the source of fatigue in individuals with KOA is central or peripheral is unclear which may be due to maladaptive neuroplastic changes that occur with KOA. To assess and compare the mechanisms for loss of force with a prolonged walk in individuals with KOA we will use transcranial magnetic stimulation to measure motor cortex excitability and inhibition (Aim 3). To test these hypotheses, data will be gathered on 2 groups of 10 men and 10 women: KOA (65-80 years) and older healthy controls (70-80 years). Both groups will be relatively sedentary, which will be verified quantitatively using accelerometry. In this cross-sectional study design, we will implement our new physiologically and clinically relevant 30-minute treadmill walk to induce knee extensor muscle fatigue and then quantify the response with measures of gait mechanics, electromyography, physical performance, and motor cortex excitability. The problem to be addressed, muscle fatigue in KOA, and its impact on mobility is significant and currently prevents many older adults from achieving an optimal health span. Understanding the mechanisms underlying changes in physical function, such as muscle fatigue in individuals with KOA will allow for a better understanding of how to optimize interventions in this population. The completion of the project and the proposed training plan activities including skill development in new experimental and advanced computational approaches as well as professional development activities will have a significant, positive impact on the development of the PI as an independent researcher, contributing to the stated goals of the NIH to enhance training of a diverse work force.

PROJECT NARRATIVE Knee osteoarthritis results in more years lived with disability compared to any other musculoskeletal condition representing a critical public health problem. By determining the biomechanical consequences of muscle fatigue in older adults with knee osteoarthritis, this project will address a knowledge gap related to the mechanisms for this disability. Our mechanistic investigation of muscle fatigue in an osteoarthritic, aging population will identify promising targets for interventions to mitigate or prevent fatigue and related mobility declines, as such, this project is highly relevant to the missions of NIH and NIA.