Fatigue is a common and important symptom among the elderly that is associated with a several-fold increase in disability and mortality. Because ATP is absolutely required to fuel normal muscle contractile function and fatigue has been conceptualized as a state of energy deficiency, an approach to characterizing bioenergetics in older subjects with fatigue is both logical and compelling. We propose here a muscle bioenergetics fatigability test that employs standardized, graded exercise conducted to performance fatigue coupled with 31P magnetic resonance spectroscopy so as to relate the level, duration and intensity of activity with fatigue symptoms and with exercising skeletal muscle bioenergetics, including repeated measures of high-energy phosphate levels, inorganic phosphate accumulation, and intracellular pH. In addition, potential mechanisms responsible for changes in metabolite levels will be studied by measuring maximal oxidative capacity, intracellular lipid content, and by magnetization transfer techniques, developed in our laboratory, to determine the rate of ATP production via creatine kinase, the primary muscle energy reserve reaction. These parameters will also be related to global indices of fatigue and cardiovascular fitness, to systemic inflammatory biomarkers, and to local factors including muscle mass and blood flow. In collaboration with the NIA BLSA populations we propose to test the hypotheses that 1) at similar workloads, muscle high-energy phosphates are reduced and Pi increased in older subjects with high, as compared to those with low, fatigability, that 2) performance fatigue occurs at the same energetic threshold but at lower workload/activity in those with high fatigability, and that 3) some responsible mechanisms for performance fatigue-related changes in high energy phosphate levels can be identified. This novel and potentially transformative approach will offer for the first time a means to objectively identify increased muscle fatigabilit, to define the role of reduced muscle energy metabolism in aging-associated fatigability, to explore responsible mechanisms, and to provide a standardized method to assess the impact of future interventions on the bioenergetic profile in older individuals with performance fatigue.

Public Health Relevance

Fatigue or tiredness predicts disability and death in older individuals. Because fatigue is considered an energy-deficient state, we are proposing a muscle energetics fatigability test to study the role of altered energy metabolism in causing fatigue in older individuals. An objective means of quantifying the energetic basis of fatigability is needed and may eventually be useful in evaluating the effectiveness of future strategies to combat fatigue and increased fatigability.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG045634-02
Application #
8712312
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Eldadah, Basil A
Project Start
2013-08-15
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$157,500
Indirect Cost
$32,500
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218