A Novel Mechanism for Sarcopenia in Chronic Kidney Disease

慢性肾脏病肌肉减少症的新机制

• 批准号: 10265352
• 负责人: Richard Joseph Johnson
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265352
• 关键词: AMP Deaminase; Adenosine Monophosphate; Affect; Aging; American; Animals; Automobile Driving; Biological Markers; Biological Process; Body Composition; Cachexia; Catabolism; Cell physiology; Chronic Kidney Failure; Code; Complication; Data; Deaminase; Diabetes Mellitus; Diet; Disease; Elderly; Enzymes; Exercise Tolerance; Female; GDF8 gene; General Population; Generations; Growth; Health; Impairment; Individual; Inflammation; Insulin Resistance; International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10); Intramuscular; Kidney; Kidney Diseases; Knockout Mice; Laboratories; Lead; Mediating; Metabolic acidosis; Metabolic syndrome; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle; Muscular Atrophy; Obesity; Oxidative Stress; Pathogenesis; Pathway interactions; Phenotype; Play; Population; Prevalence; Protein Isoforms; Protein Kinase; Proteins; Renal function; Risk; Role; Secondary to; Skeletal Muscle; System; Testing; Therapeutic; Ubiquitin; Uric Acid; Veterans; Veterans Health Administration; aging population; cost; cost estimate; energy balance; falls; frailty; functional decline; functional loss; improved; innovation; inorganic phosphate; insight; insulin sensitivity; interest; male; military veteran; mortality; mouse model; muscle form; novel; novel strategies; nutrition; overexpression; physical inactivity; preservation; prophylactic; renal damage; sarcopenia; uptake; wasting

Sarcopenia (muscle wasting) is a crippling condition that affects 25% of the aging population and even a greater percentage of subjects with chronic kidney disease (CKD), and is disproportionately high among veterans. Now recognized as a disease entity with its own ICD-10 code, it is associated with increased mortality and carries an annual US cost estimated to be more than 11.8 billion dollars and yet there is very little known of its pathogenesis or treatment. Sarcopenia is common in the aging population, especially those with obesity and diabetes. However, one population that commonly suffers from sarcopenia are those individuals suffering from chronic kidney disease, where both young and old are affected. It is now recognized that the disease does not result simply from poor nutrition and physical inactivity, but is often driven by inflammation and oxidative stress that can progress to protein-energy wasting, frailty and cachexia. The biological processes that are involved include effects of metabolic acidosis to stimulate protein catabolism from activation of the ubiquitin system, overexpression of myostatin that inhibits muscle growth, effects of insulin resistance, and other mechanisms. While much has been learned about these basic cellular processes involved in sarcopenia, here we present a novel hypothesis suggesting that the enzyme AMP deaminase 1 (AMPD1) may have a central role in causing sarcopenia by both regulating intracellular energy (ATP) levels and driving inflammation and oxidative stress. Using a model of chronic kidney disease in mice (remnant kidney model on a high protein diet), we have documented that the animals develop sarcopenia and in preliminary studies that sarcopenia does not occur in mice lacking AMPD1 with equivalent kidney damage. Here we will extend our studies to determine the effect of blocking AMPD1 in both male and female and both young and old mice with kidney disease, in association with extensive phenotyping including exercise tolerance, and studies of energy balance and body composition. Second we will explore the mechanisms by which AMPD1 activation causes inflammation, focusing on the role of uric acid and inhibition of AMP activated protein kinase. Finally, we will explore the basis underlying the activation of AMPD1 in chronic kidney disease, with an emphasis on the role of intracellular phosphate depletion and insulin resistance. If we identify activation of AMPD1 as a cause of sarcopenia and show that it is driven by insulin resistance, intracellular phosphate depletion and uric acid generation, we will not only identify a mechanism driving a severe complication of chronic kidney disease but also a potential way to intervene both prophylactically and therapeutically. Such a discovery would be of great help to all individuals with chronic kidney disease, and would have a big impact on Veterans and the Veteran Health Administration.

肌肉减少症（肌肉浪费）是一种残酷的疾病，影响了人口老龄化甚至一个 慢性肾脏疾病（CKD）的受试者比例更大，并且在 退伍军人。现在被公认为具有其自身ICD-10代码的疾病实体，它与增加有关 死亡率和每年的美国成本估计超过118亿美元，但是很少 已知其发病机理或治疗。肌肉减少症在老龄化的人口中很常见，尤其是那些 肥胖和糖尿病。但是，一个通常患有肌肉减少症的人群是那些人 患有慢性肾脏疾病，患有年轻人和老年人。现在认识到 疾病不是仅仅是由于营养和身体不良而导致的，但通常是由炎症驱动的 以及可以发展为蛋白质能量浪费，脆弱和恶病质的氧化应激。生物过程 所涉及的包括代谢性酸中毒的作用刺激激活蛋白 泛素系统，抑制肌肉生长的肌抑制素的过表达，胰岛素抵抗的影响和 其他机制。尽管有关肌肉减少症涉及的这些基本细胞过程的知识已有很多。 在这里，我们提出了一个新的假设，表明酶AMP脱氨酶1（AMPD1）可能具有 通过调节细胞内能（ATP）水平和驱动炎症来引起肌肉减少症的中心作用 和氧化应激。在小鼠中使用慢性肾脏疾病模型（高蛋白质上的残留肾脏模型 饮食），我们已经记录了动物发展肌肉减少症，并且在初步研究中表明肌肉减少症 在缺乏同等肾脏损伤的AMPD1的小鼠中不会发生。在这里，我们将把研究扩展到 确定在男性和女性中阻塞AMPD1的效果以及肾脏的年轻和老鼠 疾病，与广泛的表型合作，包括运动耐受性和能量平衡的研究 和身体成分。第二，我们将探索AMPD1激活引起的机制 炎症，重点是尿酸的作用和抑制AMP活化蛋白激酶的作用。最后，我们会的 探索慢性肾脏疾病中AMPD1激活的基础，并重点 细胞内磷酸盐耗竭和胰岛素抵抗。如果我们确定AMPD1的激活是 肌肉减少症并表明它是由胰岛素抵抗，细胞内磷酸盐消耗和尿酸驱动的 一代，我们不仅会确定一种驱动慢性肾脏疾病严重并发症的机制，而且还 这也是一种预防和治疗的潜在方法。这样的发现将是很棒的 帮助所有患有慢性肾脏疾病的人，并将对退伍军人和退伍军人产生重大影响 卫生管理。