Skeletal muscle dysfunction in persons with chronic kidney disease

慢性肾病患者的骨骼肌功能障碍

• 批准号: 8706862
• 负责人: Baback Roshanravan
• 金额: $ 17.02万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706862
• 关键词: Adult; Aerobic Exercise; Area; Award; Biochemistry; Biological Markers; Cellular Stress; Cessation of life; Chronic Kidney Failure; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cohort Studies; Complication; Data; Data Collection; Dialysis procedure; Elderly; Epidemiologic Studies; Epidemiology; Exercise; Fatty acid glycerol esters; Foundations; Functional disorder; Future; Generations; Goals; High Prevalence; Hospitalization; Human; Image; Individual; Insulin Resistance; Intervention; Intervention Trial; Investigation; K-Series Research Career Programs; Kidney Diseases; Light; Link; Magnetic Resonance Spectroscopy; Measurement; Measures; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Metabolic; Metabolism; Methods; Mitochondria; Morbidity - disease rate; Muscle; Muscle Contraction; Muscle function; Nephrology; Optics; Organ; Outcome; Outcomes Research; Oxidative Stress; Oxygen; Oxygen Consumption; Patients; Performance; Persons; Phenotype; Physical Function; Physical activity; Physiology; Research; Research Design; Research Personnel; Respiration; Sentinel; Series; Skeletal Muscle; Solid; Spectrum Analysis; Testing; Time; Training; Universities; Washington; base; cohort; disability; disorder control; experience; frailty; functional disability; improved; insulin sensitivity; member; middle age; mitochondrial dysfunction; mortality; multidisciplinary; muscle form; muscle metabolism; novel; patient oriented; pilot trial; programs; prospective; public health relevance; research study; sarcopenia; strength training; sugar; tool; translational study

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.

描述（由申请人提供）：这是华盛顿大学高级肾脏科临床研究员Baback Roshanravan博士颁发的申请。 Roshanravan博士正在建立自己的年轻研究者，从事以患者为导向的临床研究，重点介绍了慢性肾脏疾病（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的研究经验：（1）转化研究设计调查了与CKD中与骨骼肌肉功能障碍相关的代谢障碍和功能障碍； （2）干预试验设计和纵向数据收集； （3）测量CKD中线粒体功能障碍的磁共振光谱和光谱（MRS/OS）的分析和解释； （4）针对CKD中肌肉功能障碍研究的生理学，代谢，生物化学的高级培训。为了实现这些目标，他召集了一个导师团队，其中包括他的主要导师Bryan Kestenbaum博士，这是全国认可的生物标志物研究人员；和三位合作者：乔纳森·希梅尔法尔布（Jonathan Himmelfarb）博士，肾脏疾病患者的转化和成果研究领导者；国际代谢成像专家凯文·康利（Kevin Conley）博士； CKD代谢领域的专家Ian de Boer博士。骨骼肌功能障碍（Sarcopenia）是CKD识别较低的靶器官并发症，具有严重的残疾，住院和死亡的不良临床后果。该提案中的肌肉减少症是由代谢和骨骼肌质量下降或功能降低相关的身体功能受损而定义的。骨骼肌组织依靠线粒体有效利用氧气产生ATP。线粒体能量受损是CKD中肌肉减少症的中心机制。我们提出了一系列研究，旨在阐明未用透析治疗的CKD患者的肌肉减少症的病理生理学。首先，我们将使用MRS/OS在既定的CKD患者队列中使用MRS/OS来测量骨骼肌线粒体功能。其次，我们将检验假设，即CKD患者的线粒体功能障碍与代谢障碍（氧化应激和胰岛素抵抗）和身体功能受损（身体表现，身体活动和疲劳性）有关。第三，我们将对抗药性训练和有氧运动的联合抗性训练进行促进试验，以评估骨骼肌线粒体功能，代谢和身体机能的变化。我们假设运动会改善CKD患者的线粒体功能和身体功能。如果成功，这些实验将确定与CKD相关肌肉减少症的新型病理生理机制。拟议的培训将在肌肉代谢和功能中为独立研究者提供强大的初步数据和坚实的基础。具体而言，它将为未来研究线粒体功能，身体功能与CKD患者的临床结果的前瞻性关联提供基础。