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: 10671682
• 负责人: Baback Roshanravan
• 金额: $ 65.09万
• 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/10671682
• 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; Health; Heart failure; Human; Hydrogen Chloride; Hyperinsulinism; Hypertension; Impairment; Insulin; 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; Physical Endurance; Physical Function; Placebo Control; Placebos; Polymers; Population; Proteins; Quality of life; Questionnaires; Randomized; Risk; Serum; Severities; Skeletal Muscle; Sodium; Sodium Bicarbonate; Standardization; Testing; Time; Translating; Walking; Work; 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; pharmacologic; randomized trial; randomized, clinical trials; 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.

项目总结和摘要 慢性肾脏疾病（CKD）是高度流行的，影响14%的美国人口， 发病率高，生活质量下降。CKD老年人确定维持功能性 独立是他们的首要任务。骨骼肌健康对移动性至关重要，也是一个未被充分认识的目标 代谢性酸中毒（MA）和蛋白质能量消耗的CKD。骨骼肌耐力提供了一个窗口 肌肉代谢健康和肌肉质量。肌肉线粒体代谢是肌肉和骨骼肌的核心。 步行耐力从碳水化合物和脂肪中提供能量，为反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）一直被认为是导致骨骼肌萎缩的主要机制 和外周胰岛素抵抗。骨骼肌线粒体代谢被认为是一个主要的 外周胰岛素敏感性和肌肉质量的决定因素，但很少有人知道MA对 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、耐力低和肌肉萎缩。 萎缩使用体内31磷磁共振波谱（31 P MRS），我们表明， CKD的存在和严重程度与受损的肌肉线粒体生成 ATP转化为步行耐力差。我们还发现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， 在随机临床试验中的身体功能。尽管线粒体功能对肌肉的重要性 然而，由于健康状况不佳，尚不清楚MA的治疗是否有益于CKD中的肌肉线粒体功能、肥胖或耐力。 拟议的项目将使用精确的体内31 P MRS和外周胰岛素的金标准检测 通过高胰岛素正葡萄糖钳夹技术检测MA的病理生理学和低耐力的敏感性， CKD和MA的碱疗法临床试验。我们将比较维维莫或低剂量碳酸氢钠， 在一项多中心、随机、双模拟、安慰剂对照、交叉试验设计中，在102例受试者中使用安慰剂 中重度CKD和MA。首先，我们将测试3个月的碱疗法的疗效， 在一项随机研究中，维米尔或低剂量碳酸氢钠与安慰剂对肌肉代谢健康的影响 MA的交叉试验。第二，比较Veverimer或低剂量碱疗法3个月的疗效 碳酸氢钠与安慰剂对改善MA患者身体耐力的影响。我们的理论是， 低体力耐力的治疗目标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的策略将提高运动耐量，从而有效地参与 生活方式干预改善CKD患者的生活质量。