Exercise intolerance and rapid skeletal muscle energetic decline in human age-associated frailty

ARTICLE: Exercise intolerance and rapid skeletal muscle energetic decline in human age-associated frailty

AUTHORS: Sabra C. Lewsey, Kilian Weiss, Michael Schär, Yi Zhang, Paul A. Bottomley,3 T. Jake SamuelQian-Li XueAngela SteinbergJeremy WalstonGary Gerstenblith, and Robert G. Weiss

JOURNAL: JCI Insight. 2020 Sep 17;141246. doi: 10.1172/jci.insight.141246. Online ahead of print.


Background: Physical frailty in older individuals is characterized by subjective symptoms of fatigue and exercise intolerance (EI). Objective abnormalities in skeletal muscle (SM) mitochondrial high-energy phosphate (HEP) metabolism contribute to EI in inherited myopathies, but their presence or link to EI in the frail older adult is unknown.

Methods: Three groups of ambulatory, community-dwelling adults with no history of significant coronary disease were studied: frail, older individuals (FO, 81±2.7 years, mean±SEM), non-frail, older individuals (NFO, 79±2.0 years), and healthy middle-aged controls (CONT, 51±2.1 years). Lower extremity SM HEP levels and mitochondrial function were measured with 31P magnetic resonance (MR) techniques during graded, multistage plantar flexion exercise (PFE). EI was quantified by six-minute walk and peak oxygen consumption during cardiopulmonary testing (peak-VO2).

Results: During graded exercise, frail older (FO), non-frail older (NFO), and healthy middle-aged individuals all fatigued at similar SM HEP levels measured by 31P MR. However, FO fatigued fastest with several-fold higher rates of PFE-induced HEP decline, which correlated closely with shorter exercise duration in the MR scanner and with six-minute walk distance and lower peak oxygen consumption on cardiopulmonary testing (p<0.001 for all). SM mitochondrial oxidative capacity was lower in older individuals and correlated with rapid HEP decline but less closely with EI.

Conclusions: Several-fold faster skeletal muscle energetic decline during exercise occurs in frail older individuals and correlates closely with multiple measures of EI. Rapid energetic decline represents an objective, functional measure of SM metabolic changes and a potential new target for mitigating frailty-associated physical limitations.

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