Skeletal muscle function and mitochondrial metabolism in non-diabetic CKD

描述(由申请人提供)：骨骼肌是慢性肾脏疾病(CKD)的毁灭性靶标，通过改变代谢和体能表现对发病率和死亡率产生重大影响。先前的研究表明，在肥胖和糖尿病患者中，骨骼肌在葡萄糖稳态中起着重要的作用，其基础是线粒体代谢。不幸的是，非糖尿病CKD患者骨骼肌功能障碍与胰岛素抵抗之间存在关联的证据有限。几项针对社区老年CKD患者的观察性研究表明，体能能力下降与肾功能障碍程度有关，但在非透析的中年CKD患者中，体能能力与胰岛素抵抗和线粒体代谢的关系尚不清楚。这个项目的具体目标有两个方面。我们的第一个目标是在整个器官和亚细胞水平上研究中晚期非糖尿病CKD患者骨骼肌功能障碍的决定因素。我们将通过与华盛顿大学代谢成像翻译中心的合作，使用标准化的体能测量方法、体力活动的数字加速度计评估以及创新技术，使用磁共振光谱学和光谱学作为了解骨骼肌线粒体能量学的窗口。我们的第二个目标是通过金标准的正常血糖钳夹试验检查慢性肾脏疾病患者骨骼肌功能障碍和胰岛素抵抗之间的关系。为了帮助在计划的时间内成功完成这个项目，申请者将已经接受了高级流行病学方法的正式培训，包括研究设计、多变量回归建模、倾向评分和归因。在他的调查期间，他将与国际知名的肌肉力学和代谢成像专家合作，在肌肉力学和能量学方面获得宝贵的见解。他将参加肌肉生理学和生物化学课程，并参加由糖尿病内分泌研究中心主办的线粒体代谢中心的线粒体代谢研讨会。这一培训将使申请者朝着成为一名专门研究慢性肾脏病骨骼肌功能障碍的独立研究员的目标前进。更好地了解骨骼肌功能障碍在慢性肾脏病中的作用将有助于将尿毒症的代谢后果与功能损害以及心血管发病率和死亡率联系起来。最终，阐明CKD对线粒体功能的影响将确定一种新的机制，并为未来针对CKD线粒体功能障碍的大规模流行病学研究和临床试验提供经验基础。 公共卫生相关性：慢性肾脏疾病(CKD)是一种高分解代谢和炎症状态，影响多个器官，具有糖尿病的许多代谢特征，包括胰岛素抵抗。CKD的一个特别具有破坏性且未得到充分认识的目标是骨骼肌。骨骼肌功能障碍导致糖代谢异常，其基础是线粒体代谢。了解慢性肾脏病尿毒症与骨骼肌功能障碍在体能、胰岛素抵抗和线粒体能量方面的关系，将有助于将慢性肾脏病的代谢影响与功能后果联系起来。这一认识将最终确定一种新的机制，并为未来针对慢性肾脏病线粒体功能障碍的大规模流行病学研究和临床试验提供经验基础。

DESCRIPTION (provided by applicant): Skeletal muscle is a devastating target of chronic kidney disease (CKD) with significant impact on morbidity and mortality through altered metabolism and physical performance. Skeletal muscle plays an important role in glucose homeostasis with a basis in mitochondrial metabolism suggested by prior studies in obese and diabetic patients. Unfortunately the evidence for an association between skeletal muscle dysfunction and insulin resistance in non-diabetic CKD is limited. Several observational studies in community-dwelling elderly patients with CKD have shown decreased physical performance associated with degree of renal dysfunction, but the association of physical performance with insulin resistance and mitochondrial metabolism remains unclear in non-dialysis middle-aged CKD patients. The specific aims of this project are two fold. Our first aim is to examine the determinants of skeletal muscle dysfunction in moderate to advanced non-diabetic CKD both at the whole organ and at the subcellular level. We will be employing standardized physical performance measures along, digital accelerometry assessment of physical activity, and innovative technology through collaboration with the University of Washington Translational Center for Metabolic Imaging using magnetic resonance spectroscopy and optical spectroscopy as a window into skeletal muscle mitochondrial energetics. Our second aim is to examine the relationship between skeletal muscle dysfunction and insulin resistance among persons with chronic kidney disease using gold-standard euglycemic clamp testing. To help successfully complete this project in the planned period, the applicant will have already obtained formal training in advanced epidemiologic methods, including study design, multivariable regression modeling, propensity scoring, and imputation. During his investigation he will gain valuable insight in to muscle mechanics and energetics in collaboration with internationally renowned experts in muscle mechanics and metabolic imaging. He will take courses in muscle physiology and biochemisty and attend seminars on mitochondrial metabolism at the Mitochondrial Metabolism Center sponsored by the Diabetes Endocrine Research Center. This training will advance the applicant towards his goal of becoming an independent investigator specializing in skeletal muscle dysfunction in CKD. A better understanding of the role of skeletal muscle dysfunction in CKD will help link the metabolic consequence of uremia with functional impairment as well as cardiovascular morbidity and mortality. Ultimately, elucidation of the effects of CKD on mitochondrial function will identify a novel mechanism and provide an empiric basis for future large epidemiologic studies and clinical trials targeting mitochondrial dysfunctio in CKD. PUBLIC HEALTH RELEVANCE: Chronic kidney disease (CKD) is a hypercatabolic and inflammatory state with impact on multiple organs sharing many metabolic features of diabetes including insulin resistance. A particularly devastating and underrecognized target of CKD is skeletal muscle. Skeletal muscle dysfunction leads to abnormal glucose homeostasis with a basis in mitochondrial metabolism. Understanding the relationship between uremia of chronic kidney disease and skeletal muscle dysfunction in terms of physical performance, insulin resistance and mitochondrial energetics will help link the metabolic impact of CKD with the functional consequence. This understanding will ultimately identify a novel mechanism and provide an empiric basis for future large epidemiologic studies and clinical trials targeting mitochondrial dysfunction in CKD.