HUMAN SKELETAL MUSCLE MITOCHONDRIA: CHANGES WITH AGING AND ROLE IN SARCOPENIA

Sarcopenia, the age-related progressive loss of muscle mass, strength and physical function, is a well-established risk factor for several negative health-related conditions. While cellular, systemic and lifestyle factors have shown to be associated with the onset and development of sarcopenia, the primary mechanisms contributing to this process are still uncertain, especially in humans. Among the cellular factors hypothesized to play a role on muscle aging is mitochondrial function. Several questions, however, remain. The purpose of study 1 of this dissertation was to investigate the association between mitochondrial capacity and chronological aging. Percutaneous biopsies of the vastus lateralis were obtained from 68 healthy men and women with a wide range of age (20-88yrs), body mass index (BMI, 19-47kg/m2) and cardiorespiratory fitness (VO2max: 1.08-5.04L/min). Mitochondrial capacity was evaluated through mitochondrial respiration in permeabilized myofibers and expression of proteins that mediate mitochondrial fusion, fission and autophagy. Mitochondrial respiration and expression of mitochondrial quality control proteins were elevated in young physically active individuals, but were similar among sedentary young, middle-aged and older subjects. The findings of this study suggest that mitochondrial capacity is not influenced by chronological age per se, but is closely related to BMI and cardiorespiratory fitness. Study 2 was performed to investigate the association between mitochondrial function and sarcopenia in very old adults. Specifically, the association between mitochondrial respiration and myofiber cross-sectional area, intramyocellular lipid content, and physical function were evaluated. Percutaneous biopsies from vastus lateralis were collected from 41 very old men and women (85-95yrs). Myofiber cross-sectional area and intramyocellular lipid content were evaluated histologically. Grip strength was tested by a handheld dynamometer, and knee extension torque was evaluated by an isokinetic dynamometer. Physical function was evaluated by physical performance tests including the multiple chair stand, standing balance, and gait speed. Mitochondrial respiration explained a significant amount of variation in grip strength and knee extension peak torque, and was associated with preferred gait speed. The findings of this study suggest that mitochondrial capacity plays a role in sarcopenia among the very old, but that other factors secondary to aging, including decreased physical activity and higher adiposity may influence this association