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.

项目摘要和摘要 慢性肾脏疾病（CKD）高度普遍，影响美国14％的人口 大量发病率和生活质量降低。患有CKD的老年人确定功能的维护 独立作为他们的首要任务。骨骼肌健康对移动性和未经认可的目标至关重要 CKD中的代谢性酸中毒（MA）和蛋白质能量浪费。骨骼肌耐力提供了一个窗户 进入肌肉代谢健康和肌肉质量。肌肉线粒体代谢是肌肉和 步行耐力从碳水化合物和脂肪中提供能量，为重复的肌肉收缩提供动力。我们 表现出代谢性酸中毒和肌肉肥胖作为肌肉线粒体功能的主要决定因素。 代谢性酸中毒（MA）长期以来一直被认为是导致骨骼肌浪费的主要机制 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 决定周围胰岛素敏感性和肌肉质量的决定因素，但对MA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有缺陷 增强肥胖性和脂肪毒性中间体，导致胰岛素抵抗，低耐力和肌肉 萎缩。使用体内31磷磁共振光谱法（31p MRS）我们表明 CKD的存在和严重程度与肌肉线粒体能力受损密切相关 ATP转化为步行不良的耐力。我们还表现出MA和肌肉肥胖是主要的 肌肉线粒体功能的决定因素。最近，非钠聚合物（Veverimer）选择性结合 胃肠道中的氯化氢安全改善了血清碳酸氢盐，并有意义地改善了 在随机临床试验中进行身体功能。尽管线粒体功能对肌肉很重要 健康，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31p MRS和外围胰岛素的金标准测试 高胰岛素血糖夹的敏感性，以探测A中MA和低耐力的病理生理学 CKD和MA中碱疗法的临床试验。我们将比较碳酸氢盐或低剂量碳酸氢钠与 安慰剂在多中心随机，双夜安慰剂对照，跨越试用设计中的安慰剂。 与中等重度CKD和MA。首先，我们将测试比较3个月的碱性治疗的功效 在随机的肌肉代谢健康方面，碳酸氢钠与安慰剂的veverimer或低剂量 马萨诸塞州的跨界试验。其次，测试比较Veverimer或低剂量的3个月碱疗法的功效 碳酸氢钠与安慰剂在改善MA的身体耐力方面。我们的理由是身份证明 低身体耐力的治疗靶标将为药理学干预的发展提供信息。 长期，我们预计治疗MA的策略将提高运动宽容，从而有效参与 生活方式干预措施改善了CKD的生活质量。