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

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 (REP) metabolism contribute to EI in inherited myopathies; however, their presence or link to EI in the frail older adult is unknown. METHODS. Here, we studied 3 groups of ambulatory, community-dwelling adults with no history of significant coronary disease: frail older (FO) individuals (81 +/- 2.7 years, mean +/- SEM), nonfrail older (NFO) individuals (79 +/- 2.0 years), and healthy middle-aged individuals, who served as controls (CONT, 51 +/- 2.1 years). Lower extremity SM REP levels and mitochondrial function were measured with P-31 magnetic resonance (MR) techniques during graded multistage plantar flexion exercise (PFE). El was quantified by a 6-minute walk (6MW) and peak oxygen consumption during cardiopulmonary testing (peak VO2). RESULTS. During graded exercise. FO, NFO, and CONT individuals all fatigued at similar SM HEP levels, as measured by P-31-MR. However, FO individuals fatigued fastest, with several-fold higher rates of PFE-induced HEP decline that correlated closely with shorter exercise duration in the MR scanner and with 6MW 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 REP decline but less closely with EI. CONCLUSION. Several-fold faster SM energetic decline during exercise occurs in FO 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.