Mechanisms of Interventions to Ameliorate Sarcopenia in Chronic Kidney Disease

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Chronic kidney disease (CKD) affects 20 million Americans and contributes to sarcopenia, which includes muscle loss (atrophy), muscle weakness and/or reduced mobility. Sarcopenia is clinically important as it contributes to increased fall risk, morbidity and mortality. Although, the pathophysiology of sarcopenia in CKD remains unknown, sarcopenia in CKD is likely due to aberrant signaling for muscle metabolism, catabolism, and regeneration. We propose that central components of these to sarcopenic alterations are impaired skeletal muscle mitochondria and increased myostatin. The overall goal of this proposal is to test the hypothesis that exercise or myostatin blocking therapy prevents atrophy, but exercise is needed to improve skeletal muscle metabolism and function in CKD. This goal will be accomplished through a combination of pre- clinical experiments using our established model of progressive CKD (the Cy/+ rat), pharmacological and non- pharmacological interventions. We will assess mitochondrial function using high resolution respirometry, aerobic capacity via VO2max assessment, muscle strength and fatigue assessed by electrical stimulation and maximal voluntary grip strength, muscle mass, and overall physical activity levels. The interdisciplinary mentoring team and I are perfectly positioned to undertake this translational work based on our clinical and preclinical expertise in CKD, myostatin and skeletal muscle. In aim 1 we will assess the efficacy of moderate and high intensity AEROBIC exercise in improving skeletal muscle metabolism and aerobic capacity in CKD rats. In aim 2, we will assess the efficacy of moderate and high intensity RESISTANCE training on skeletal muscle size and strength in CKD rats. In aim 3 we will assess the efficacy of myostatin blocking therapy compared to optimal exercise in increasing muscle mass, muscle metabolism and function. The current proposal will develop a number of skills required to be a successful, independent translational research. While my long term goal is patient implementation, building a solid basic science skill set will allow for parallel studies that provide a mechanistic understanding. If these studies show efficacy in benefiting skeletal muscle function and/or mass, these treatments could be rapidly translated into the clinical setting.