UC Berkeley

Skeletal muscle cellular function relies on mitochondrial oxidative phosphorylation and maintenance of the mitochondrial reticulum through naturally occurring fusion and fission. A key molecule in oxidative phosphorylation is lactate, a product of glycolysis formed under aerobic conditions and a major energy source, gluconeogenic precursor, and a signaling molecule. With age progression, mitochondrial function decreases in part due to elevated oxidative damage and increased mitochondrial fission, resulting in the inability to metabolize different energy substrates or “metabolic inflexibility”. Damage caused by oxidative stress, such as lipid peroxidation, leads to altered mitochondrial dynamics, oxidative cell death, and an increased risk of age-related diseases such as sarcopenia. Peroxiredoxin 6 (Prdx6) is a bifunctional enzyme capable of repairing peroxidized membranes and mice lacking Prdx6 exhibit sarcopenia-like phenotypes suggesting an age-related effect of Prdx6. The purpose of this dissertation was to understand the effects of aging on lactate metabolism and mitochondrial dysfunction while studying the role of oxidative stress as a potential driver for age-related changes to mitochondrial metabolism. I hypothesized that aging impairs lactate metabolism in humans while promoting mitochondrial dysfunction in skeletal muscle-derived cells and that oxidative stress derived from age-related reductions in mitochondrial Prdx6 is a primary driver of this dysfunction. The effect of age on the Postprandial Lactate Shuttle and aging-related metabolic inflexibility and mitochondrial dysfunction was revealed. These findings collectively contribute to our understanding of the mechanisms underlying age-related mitochondrial dysfunction, emphasizing the critical role of Prdx6 in preserving mitochondrial integrity in skeletal muscle. These insights pave the way for future research and interventions aimed at improving mitochondrial health in the aging population. Here, I discuss how aging affects skeletal muscle, lactate metabolism, and mitochondrial function, and how oxidative stress is a primary driver of such effects in skeletal muscle.