Bioenergetics and fatigability in older individuals

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DESCRIPTION (provided by applicant): 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.