Mitochondrial Energetics

Skeletal muscle metabolic health is critical for mobility and an underrecognized target of metabolic acidosis in chronic kidney disease. Impaired muscle mitochondrial metabolism underlies poor physical endurance increasing the risk of mobility disability. The proposed project will use precise in vivo tools to study the pathophysiology of poor physical endurance in a clinical trial treating metabolic acidosis among persons living with chronic kidney disease.

Diminished use of skeletal muscle, such as occurs with many chronic diseases (e.g., heart failure or cancer cachexia), denervation, bedrest, immobilization (e.g., limb casting or bracing), etc., is a common clinical condition affecting untold millions of individuals each year. Such disuse leads to a rapid decline in muscle fiber area and hence whole muscle size, contributing to a decrease in strength, speed, and power as well as alterations in energy metabolism. Collectively, these changes lead to reduced physical function and contribute to the seriousness of any disease, illness (e.g., pneumonia), surgery (e.g., joint replacement), or injury (e.g., broken bone) accompanied by decreased muscular activity. Currently, there are no effective pharmacological treatments to prevent disuse-associated muscle wasting in humans. The above-described effects of disuse appear to be due, at least in part, to a decrease in nitric oxide (NO) bioavailability. Reduced synthesis of NO and/or increased NO destruction (due to increased production of oxygen free radicals) likely contributes to the mitochondrial changes, energetic abnormalities, and muscle atrophy resulting from immobilization. The objective of this study is to investigate the potential benefits of dietary nitrate supplementation on immobilization-induced changes in muscle contractile function and mitochondrial respiratory capacity in young healthy men. Our disuse-induced muscle atrophy model will involve wearing a knee brace for a period of 14 d.