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（肌肉萎缩）是一种严重的疾病，影响25%的老龄人口，甚至是一个 慢性肾脏疾病（CKD）受试者的比例更高， 老兵现在被认为是一种疾病实体，有自己的ICD-10编码，它与增加的 死亡率和携带美国每年的成本估计超过118亿美元，但很少有 了解其发病机理或治疗方法。肌肉减少症在老年人群中很常见，尤其是那些 肥胖和糖尿病。然而，通常患有肌肉减少症的一个群体是那些个体， 患有慢性肾病，无论老少都受到影响。现在人们认识到， 疾病不仅仅是由于营养不良和缺乏身体活动造成的，而且往往是由炎症引起的 以及氧化应激，其可发展为蛋白质能量消耗、虚弱和恶病质。的生物过程 包括代谢性酸中毒的影响，以刺激蛋白质催化剂的激活， 泛素系统，抑制肌肉生长的肌生长抑制素的过表达，胰岛素抵抗的影响，以及 其他机制。虽然已经了解了很多关于肌肉减少症的这些基本细胞过程， 在这里，我们提出了一个新的假设，表明酶AMP脱氨酶1（AMPD 1）可能有一个 通过调节细胞内能量（ATP）水平和驱动炎症，在引起肌肉减少症中发挥核心作用 和氧化应激。使用小鼠慢性肾脏疾病模型（高蛋白水平下的残肾模型）， 饮食），我们已经记录了动物发生肌肉减少症，并且在初步研究中，肌肉减少症 在缺乏AMPD 1的小鼠中不发生，具有等同的肾损伤。在这里，我们将扩展我们的研究， 确定阻断AMPD 1在雄性和雌性以及年轻和年老小鼠中的作用 疾病，与包括运动耐量在内的广泛表型相关，以及能量平衡研究 和身体组成。第二，我们将探讨AMPD 1激活导致 炎症，重点探讨尿酸的作用和AMP活化蛋白激酶的抑制作用。最后我们将 探索AMPD 1在慢性肾脏疾病中激活的基础，重点是AMPD 1在慢性肾脏疾病中的作用。 细胞内磷酸盐耗竭和胰岛素抵抗。如果我们确定AMPD 1的激活是导致 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 我们不仅将确定一种驱动慢性肾脏疾病严重并发症的机制， 这也是一种潜在的介入治疗的方法。这样的发现将是伟大的 帮助所有慢性肾病患者，并将对退伍军人和退伍军人产生重大影响。 卫生管理局。