Compared with young adults, people over the age of 65 years experience greater muscle fatigue at high contraction velocities, such as those that occur during walking. Although fatigue, or the acute decrease in maximal force or power, is a fundamental characteristic of skeletal muscle, the pathway from impaired cellular energetics, contractile function and fatigue to age-related changes in mobility function remains unknown. Mobility reduction in older adults carries an increased risk for morbidities and a poor quality of life, which in turn creates tremendous personal and societal burdens. Mobility dysfunction in older adults is associated with decrements in knee extensor muscle (KE) function. Notably, the KE of older adults exhibit a deficit in oxidative energy production in vivo, as well as greater fatigue compared with young adults. A novel means to address the clinical problem of KE fatigue and its impact on mobility in aging is to determine the fundamental molecular and cellular deficits that contribute to greater fatigue in older adults, and how these fatigue mechanisms lead to mobility dysfunction. The overall goal of our research is to provide this new knowledge and mitigate decreased mobility in our aging population. Our central hypothesis is that the KE of older adults, particularly those with mobility dysfunction, will have deficits of in vivo mitochondrial energy production that exacerbate impaired contractile function and result in greater fatigue during energetically- demanding work, including walking. To test this hypothesis, data will be gathered before and after fatiguing high-velocity contractions in 30 healthy young (30-40 yr), 30 healthy older (70-80) and 30 older (70-80) adults with mobility impairment. All groups will be relatively sedentary, which will be verified quantitatively using accelerometry. We will use an integrated and translational approach to build from the molecular to the behavioral, by measuring: intracellular energetics using non-invasive magnetic resonance (MR) spectrosopy; muscle morphology by MR imaging; single muscle fiber calcium sensitivity and myosin-actin cross-bridge kinetics during fatigue conditions; force-velocity relationships of single fibers and intact muscle; lower extremity joint mechanics, the energy cost of walking, perceived exertion and mobility tasks (chair rises, balance) before and after fatigue. We will determine the role of deficits in both energy production (Aim 1) and contractile function (Aim 2) in the greater muscle fatigue of older adults, as well as the impact of fatigue on gait mechanics, the energy cost of transport, and mobility (Aim 3). Potential sex-based differences will be evaluated in each Aim. The problem to be addressed- the causes of greater fatigue and how it impacts mobility in older adults- tackles stated goals of the NIH and NIA. Our success will have a significant, positive impact by bridging an existing knowledge gap that currently limits our ability to keep our aging population physically active and healthy. Promising targets for mitigation (e.g., aspects of contractile function or mitochondrial energetics?) will be identified and pursued in future studies.

Public Health Relevance

The proposed research will address a critical public health problem related to loss of mobility function in aging by determining the causes and consequences of greater muscle fatigue in older adults. Our innovative, multi- scale approach, which combines state-of-the-art measures from the molecular and cellular to whole-body and behavioral levels, will provide the new information necessary to bridge an existing knowledge gap and thus enable translation of basic science to public health. As such, this project is highly relevant to the missions of NIH and NIA. Our outcomes will identify promising targets for rehabilitation designed to mitigate or prevent decreased mobility in our aging population.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG058607-01A1
Application #
9661703
Study Section
Musculoskeletal Rehabilitation Sciences Study Section (MRS)
Program Officer
Joseph, Lyndon
Project Start
2019-08-15
Project End
2024-05-31
Budget Start
2019-08-15
Budget End
2020-05-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Massachusetts Amherst
Department
Other Health Professions
Type
Schools of Public Health
DUNS #
153926712
City
Hadley
State
MA
Country
United States
Zip Code
01035