Skeletal muscle dysfunction in persons with chronic kidney disease

描述(由申请人提供)：这是华盛顿大学肾脏病临床高级研究员Baback Roshanravan博士的K23奖项的申请。Roshanravan博士在以患者为导向的临床研究中确立了自己作为年轻研究员的地位，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)调查与慢性肾脏病骨骼肌功能障碍相关的代谢障碍和功能损害的转译研究设计；(2)干预试验设计和纵向数据收集；(3)分析和解释磁共振光谱分析和光谱分析(MRS/OS)测量慢性肾脏病患者线粒体功能障碍；(4)适应CKD肌肉功能障碍研究的生理学、新陈代谢、生化方面的高级培训。为了实现这些目标，他组建了一个导师团队，其中包括他的主要导师、国家公认的生物标记物研究员Bryan Kestenbaum博士，以及三位共同导师：肾病患者翻译与结局研究的领导者Jonathan Himmelfarb博士、国际知名的代谢成像专家Kevin Conley博士以及CKD代谢领域的专家Ian de Boer博士。骨骼肌功能障碍(骨质肌减少)是慢性肾脏病的一种未被认识的靶器官并发症，具有严重的残疾、住院和死亡等不良临床后果。在本建议中，骨质疏松症定义为与骨骼肌质量或功能降低相关的新陈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来产生三磷酸腺苷。线粒体能量学受损是慢性肾脏病肌无力的主要机制之一。我们提出了一系列研究，旨在阐明未经透析治疗的慢性肾脏病患者的石棺减少的病理生理学。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，我们将检验一种假设，即CKD患者的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(体能、体力活动和疲劳性)有关。第三，我们将进行阻力训练和有氧运动相结合的初步干预试验，以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慢性肾脏病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相关性石棺减少的新的病理生理机制。拟议的培训将在肌肉新陈代谢和功能方面提供强大的初步数据和坚实的基础，以作为独立研究人员的基础。具体地说，这将为未来研究CKD患者线粒体功能、身体功能与临床结果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.