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

代谢性酸中毒对慢性肾病患者肌肉线粒体能量学、代谢健康和身体耐力的影响

• 批准号: 10278747
• 负责人: Baback Roshanravan
• 金额: $ 66.82万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-18 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10278747
• 关键词: Affect; Alkalies; Animal Model; Bicarbonates; Binding; Biology; Carbohydrates; Cessation of life; Chronic Kidney Failure; Clinical Trials; Closure by clamp; Cross-Over Trials; Development; Dose; Elderly; Ergometry; Exercise Tolerance; Fatigue; Fatty acid glycerol esters; Functional disorder; Future; Gastrointestinal tract structure; Glucose Clamp; Gold; Health; Heart failure; Human; Hydrogen Chloride; Hypertension; Impairment; Insulin Resistance; Intervention; Investigation; K-Series Research Career Programs; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maintenance; Measures; Metabolic; Metabolic acidosis; Metabolism; Mitochondria; Morbidity - disease rate; Muscle; Muscle Contraction; Muscle Mitochondria; Muscular Atrophy; Nephrology; Obesity; Participant; Patient Self-Report; Patients; Peripheral; Persons; Pharmacology; Physical Endurance; Physical Function; Placebos; Polymers; Population; Proteins; Quality of life; Questionnaires; Randomized; Randomized Clinical Trials; Risk; Serum; Severities; Skeletal Muscle; Sodium; Sodium Bicarbonate; Standardization; Testing; Time; Translating; Walking; Work; base; disability; efficacy testing; functional independence; high risk; improved; in vivo; insulin sensitivity; insulin signaling; lifestyle intervention; lipid metabolism; mitochondrial dysfunction; mitochondrial metabolism; muscle metabolism; muscle physiology; nutrition; randomized trial; skeletal muscle wasting; therapeutic target; tool; treatment duration; trial design; wasting

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.

项目概要和摘要 慢性肾病 (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 CKD 的老年人需要维持功能 独立作为他们的首要任务。骨骼肌健康对于行动能力至关重要，也是一个未被充分认识的目标 CKD 中代谢性酸中毒 (MA) 和蛋白质能量消耗的影响。骨骼肌耐力提供了一个窗口 影响肌肉代谢健康和肌肉质量。肌肉线粒体代谢是肌肉的核心 步行耐力从碳水化合物和脂肪中提供能量，为肌肉反复收缩提供动力。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。 长期以来，代谢性酸中毒（MA）被认为是导致骨骼肌萎缩的主要机制 和 CKD 中的外周胰岛素抵抗。骨骼肌线粒体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，但人们对 MA 对外周胰岛素敏感性和肌肉质量的影响知之甚少。 肌肉线粒体功能。肌肉线粒体功能障碍导致脂质代谢缺陷 增加肥胖和脂毒性中间体，导致胰岛素抵抗、低耐力和肌肉 萎缩。使用体内 31 磷磁共振波谱 (31P MRS)，我们表明 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。 ATP 转化为步行耐力差。我们还表明 MA 和肌肉肥胖是主要的 肌肉线粒体功能的决定因素。最近一种非钠聚合物（veverimer）选择性结合 胃肠道中的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机能。尽管线粒体功能对肌肉很重要 健康方面，目前尚不清楚 MA 治疗是否有益于 CKD 患者的肌肉线粒体功能、肥胖或耐力。 拟议项目将使用精确的体内 31P MRS 和外周胰岛素金标准测试 高胰岛素正常血糖钳夹的敏感性，以探讨 MA 的病理生理学和低耐力 碱疗法治疗 CKD 和 MA 的临床试验。我们将比较维维默或低剂量碳酸氢钠 在 102 人参与的多中心随机、双模拟安慰剂对照、交叉试验设计中使用安慰剂 患有中重度 CKD 和 MA。首先我们测试3个月碱疗的疗效比较 在一项随机研究中，veverimer 或低剂量碳酸氢钠与安慰剂对肌肉代谢健康的影响 马萨诸塞州的交叉试验。二、测试3个月碱疗效果对比veverimer或低剂量 碳酸氢钠与安慰剂在改善 MA 身体耐力方面的比较。我们的理由是识别 低身体耐力的治疗目标将为药物干预措施的发展提供信息。 从长远来看，我们预计治疗 MA 的策略将提高运动耐量，从而能够有效参与 生活方式干预可改善 CKD 患者的生活质量。