Impact of metabolic acidosis on muscle mitochondrial energetics, metabolic health and physical endurance in persons with chronic kidney disease

项目摘要和摘要 慢性肾脏疾病(CKD)非常普遍，影响着14%的美国人口，导致 严重的发病率和生活质量下降。患有慢性肾脏病的老年人识别功能性维持 独立是他们的首要任务。骨骼肌健康对行动能力至关重要，也是一个被忽视的目标 慢性肾脏病的代谢性酸中毒(MA)和蛋白质能量浪费。骨骼肌耐力提供了一个窗口 肌肉新陈代谢健康和肌肉质量。肌肉线粒体新陈代谢是肌肉和 步行耐力，提供来自碳水化合物和脂肪的能量，为重复的肌肉收缩提供动力。我们 显示代谢性酸中毒和肌肉肥胖是肌肉线粒体功能的主要决定因素。 代谢性酸中毒(MA)长期以来被认为是导致骨骼肌萎缩的主要机制 CKD患者存在外周胰岛素抵抗。骨骼肌线粒体新陈代谢被认为是主要的 外周胰岛素敏感性和肌肉质量的决定因素，但对MA对 肌肉线粒体功能。肌肉线粒体功能障碍导致脂代谢缺陷 增加肥胖和脂毒中间体，导致胰岛素抵抗、低耐力和肌肉 萎缩。利用体内~(31)P磁共振波谱(31P-MRS)，我们发现 CKD的存在和严重程度与肌肉线粒体生成能力受损密切相关 三磷酸腺苷转化为行走耐力差。我们还发现MA和肌肉肥胖症是主要的 肌肉线粒体功能的决定因素。最近一种非钠聚合物(维拉帕米)选择性结合 胃肠道氯化氢安全地改善了血清碳酸氢盐，并有意义地改善 随机临床试验中的身体功能。尽管线粒体功能对肌肉很重要 健康方面，目前尚不清楚MA治疗是否有助于CKD患者的肌肉线粒体功能、肥胖或耐力。 拟议的项目将使用精确的活体31P磁共振波谱和外周胰岛素的金标准测试 高胰岛素正糖钳夹检测MA和耐力低下的敏感性 碱疗法治疗CKD和MA的临床试验。我们会将维拉帕米或低剂量的碳酸氢钠与 安慰剂在102人中的多中心随机、双模拟、安慰剂对照、交叉试验设计 中重度CKD和MA。首先，我们将测试为期3个月的碱疗法的疗效对比 维拉帕米或小剂量碳酸氢钠与安慰剂对肌肉代谢健康影响的随机对照研究 马萨诸塞州的交叉试验。第二，测试3个月碱疗法的疗效，并与维拉帕米和小剂量进行比较 碳酸氢钠与安慰剂在提高MA患者身体耐力方面的比较。我们的理由是这种认同 对低身体耐力的治疗靶点的研究将为药物干预的发展提供信息。 从长远来看，我们预计治疗MA的策略将改善运动耐量，使其能够有效地参与 生活方式干预改善慢性肾脏病患者的生活质量。

PROJECT SUMMARY AND ABSTRACT Chronic kidney disease (CKD) is highly prevalent affecting 14% of the U.S. population leading to substantial morbidity and reduced quality of life. Older adults with CKD identify maintenance of functional independence as their top priority. Skeletal muscle health is critical for mobility and an underrecognized target of metabolic acidosis (MA) and protein energy wasting in CKD. Skeletal muscle endurance provides a window into muscle metabolic health and muscle quality. Muscle mitochondrial metabolism is central to muscle and walking endurance providing energy from carbohydrates and fats to power repeated muscle contraction. We showed metabolic acidosis and muscle adiposity as the major determinants of muscle mitochondrial function. Metabolic acidosis (MA) is long believed to be the main mechanism leading to skeletal muscle wasting and peripheral insulin resistance in CKD. Skeletal muscle mitochondrial metabolism is considered a principal determinant of peripheral insulin sensitivity and muscle quality, but little is known of the impact of MA on muscle mitochondrial function. Muscle mitochondrial dysfunction leads to defective lipid metabolism augmenting adiposity and lipotoxic intermediates resulting in insulin resistance, low endurance, and muscle atrophy. Using in vivo 31Phosphorus Magnetic Resonance Spectroscopy (31P MRS) we showed that the presence and severity of CKD is strongly associated with impaired muscle mitochondrial capacity to generate ATP translating into poor walking endurance. We also showed MA and muscle adiposity are the major determinants of muscle mitochondrial function. Recently a non-sodium polymer (veverimer) selectively binding hydrogen chloride in gastrointestinal tract safely improved serum bicarbonate and meaningfully improved physical functioning in a randomized clinical trial. Despite the importance of mitochondrial function to muscle health, it is unknown if treatment of MA benefits muscle mitochondrial function, adiposity or endurance in CKD. The proposed project will use precise, in vivo 31P MRS and gold-standard testing of peripheral insulin sensitivity by hyperinsulinemic euglycemic clamp to probe the pathophysiology of MA and low endurance in a clinical trial of alkali therapy in CKD and MA. We will compare veverimer or low-dose sodium bicarbonate to placebo in a multicenter randomized, double-dummy placebo-controlled, cross-over trial design in 102 persons with moderate-severe CKD and MA. First, we will test the efficacy of 3-months of alkali therapy comparing veverimer or low dose sodium bicarbonate versus placebo on muscle metabolic health in a randomized crossover trial in MA. Second, Test the efficacy of 3-months of alkali therapy comparing veverimer or low dose sodium bicarbonate versus placebo on improving physical endurance in MA. Our rationale is that identification of therapeutic targets for low physical endurance will inform the development of pharmacologic interventions. Long term, we expect strategies treating MA will improve exercise tolerance enabling effective engagement in lifestyle interventions improving quality of life in CKD.