Skeletal muscle dysfunction in persons with chronic kidney disease

描述（由申请人提供）：这是华盛顿大学高级肾脏病临床研究员Baback Roshanravan博士的K23奖申请。Roshanravan博士是一名以患者为导向的临床研究的年轻研究者，专注于慢性肾脏疾病（CKD）对骨骼肌功能的影响。该奖项将为他提供以下领域的培训和指导研究经验：(1)研究CKD中与骨骼肌功能障碍相关的代谢紊乱和功能损伤的转化研究设计；(2)干预试验设计与纵向数据收集；(3)磁共振波谱和光谱学（MRS/OS）检测CKD线粒体功能障碍的分析与解释；(4)适应CKD肌肉功能障碍研究的生理、代谢、生物化学方面的高级训练。为了实现这些目标，他组建了一个导师团队，包括他的主要导师Bryan Kestenbaum博士，全国公认的生物标志物研究员；和三位共同导师：Jonathan Himmelfarb博士，肾病患者转化和结果研究的领导者；国际知名代谢成像专家Kevin Conley博士；Ian de Boer博士，CKD代谢领域的专家。骨骼肌功能障碍（肌肉减少症）是CKD的一个未被充分认识的靶器官并发症，具有残疾、住院和死亡的严重不良临床后果。骨骼肌减少症的定义是与骨骼肌质量或功能减少相关的代谢和身体功能受损。骨骼肌组织依靠线粒体有效地利用氧气产生ATP。线粒体能量受损是CKD中肌肉减少的主要机制。我们提出了一系列的研究，旨在阐明未接受透析治疗的CKD患者肌肉减少症的病理生理学。首先，我们将使用MRS/OS在已建立的CKD患者队列中测量骨骼肌线粒体功能。其次，我们将验证CKD患者线粒体功能障碍与代谢紊乱（氧化应激和胰岛素抵抗）和身体功能受损（身体表现、身体活动和疲劳）相关的假设。第三，我们将进行阻力训练与有氧运动相结合的先导干预试验，评估骨骼肌线粒体功能、代谢和身体功能的变化。我们假设运动可以改善CKD患者的线粒体功能和身体功能。如果成功，这些实验将确定CKD相关肌肉减少症的新的病理生理机制。建议的训练将提供强有力的初步数据和肌肉代谢和功能的坚实基础，以建立在一个独立的研究者。具体来说，它将为未来研究CKD患者线粒体功能、身体功能与临床结局的前瞻性关联提供基础。

DESCRIPTION (provided by applicant): 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.