This is an application for a K23 award for Dr. Baback Roshanravan, senior nephrology clinical research fellow at the University of Washington. Dr. Roshanravan is establishing himself as a young investigator in patient- oriented clinical research focusing on the impact of chronic kidney disease (CKD) on skeletal muscle function. This award will provide him with training and mentored research experience in the following areas: (1) Translational study design investigating metabolic disturbances and functional impairments associated with skeletal muscle dysfunction in CKD; (2) Intervention trial design and longitudinal data collection; (3) Analysis and interpretation of magnetic resonance spectroscopy and optical spectroscopy (MRS/OS) measuring mitochondrial dysfunction in CKD; (4) Advanced training in physiology, metabolism, biochemistry adapted to the study of muscle dysfunction in CKD. To achieve these objectives he has assembled a team of mentors including his primary mentor Dr. Bryan Kestenbaum, nationally recognized biomarker researcher; and three co- mentors: Dr. Jonathan Himmelfarb, leader in translational and outcomes research in persons with kidney disease; Dr. Kevin Conley, internationally renowned expert in metabolic imaging; and Dr. Ian de Boer, expert in the field of metabolism in CKD. Skeletal muscle dysfunction (sarcopenia) is an under-recognized target organ complication of CKD with substantial adverse clinical consequences of disability, hospitalization, and death. Sarcopenia in this proposal is defined by impaired metabolism and physical function associated with decreased skeletal muscle mass or function. Skeletal muscle tissue relies on mitochondria to efficiently utilize oxygen to generate ATP. Impaired mitochondrial energetics is a central mechanism of sarcopenia in CKD. We propose a series of studies designed to shed light on the pathophysiology of sarcopenia in persons with CKD not treated with dialysis. First, we will measure skeletal muscle mitochondrial function using MRS/OS among members of an established cohort of patients with CKD. Second, we will test hypothesis that mitochondrial dysfunction in persons with CKD is associated with metabolic disturbances (oxidative stress and insulin resistance) and impaired physical function (physical performance, physical activity and fatigability). Third, we will conduc a pilot intervention trial of combined resistance training and aerobic exercise to assess changes in skeletal muscle mitochondrial function, metabolism and physical function. We hypothesize that exercise leads to improvements in mitochondrial function and physical function in persons with CKD. If successful, these experiments will identify novel pathophysiologic mechanisms for CKD associated sarcopenia. The proposed training will provide strong preliminary data and solid foundation in muscle metabolism and function to build upon as an independent investigator. Specifically, it will provide a basis for future investigation of prospective associations of mitochondrial function, physical function with clinical outcomes in CKD patients.
Skeletal muscle dysfunction (sarcopenia) is an under-recognized target organ complication of CKD leading to substantial adverse clinical consequences of disability, hospitalization, and death. Skeletal muscle tissue relies on mitochondria to efficiently use oxygen to metabolize fats and sugars in order to reduce cellular stress and generate energy to power muscle contraction. The goals of this proposal are to shed light on a novel pathophysiologic mechanism of CKD associated sarcopenia by investigating: 1) if persons with CKD have decreased mitochondrial function, 2) if mitochondrial dysfunction is associated with worse metabolic derangements and impaired physical function among persons with CKD, and 3) investigate if exercise leads to improvements in mitochondrial function, metabolism, and/or physical function in persons with CKD. This understanding will ultimately identify a novel mechanism and provide a basis for future large epidemiologic studies and clinical trials targeting mitochondrial dysfunction in CKD.
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