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.

骨质疏松症(肌肉萎缩)是一种严重的疾病，影响25%的老龄化人口，甚至 患有慢性肾脏疾病(CKD)的受试者比例更高，在 退伍军人。现在被认为是一种拥有自己的ICD-10代码的疾病实体，它与 死亡率和每年在美国造成的损失估计超过118亿美元，然而 已知其发病机制或治疗方法。骨质疏松症在老龄化人口中很常见，特别是那些患有 肥胖和糖尿病。然而，通常患有骨质疏松症的人群就是这些个体。 患有慢性肾脏疾病，年轻人和老年人都会受到影响。现在人们认识到， 疾病不仅仅是营养不良和缺乏运动所致，而往往是由炎症引起的。 氧化应激可导致蛋白质能量浪费、虚弱和恶病质。生物过程 所涉及的包括代谢性酸中毒的影响，以刺激蛋白质分解代谢激活 泛素系统，抑制肌肉生长的肌肉生长抑制素过表达，胰岛素抵抗的影响，以及 其他机制。虽然关于这些与石棺减少症有关的基本细胞过程已经了解了很多， 在这里，我们提出了一个新的假说，认为AMP脱氨酶1(AMPD1)可能具有 通过调节细胞内能量(ATP)水平和促进炎症，在导致骨质疏松症中发挥核心作用 和氧化应激。采用小鼠慢性肾脏病模型(高蛋白残余肾模型 饮食)，我们已经记录了这些动物会出现石棺减少症，并且在初步研究中，石棺减少症 在缺乏AMPD1并有同等肾脏损害的小鼠中不会发生这种情况。在这里，我们将把我们的研究扩展到 阻断AMPD1对雄性和雌性及幼年和老年小鼠肾脏的影响 疾病，与广泛的表型相关，包括运动耐量和能量平衡研究 和身体成分。第二，我们将探索AMPD1激活导致 炎症，重点是尿酸的作用和抑制AMP活化的蛋白激酶。最后，我们会 探讨AMPD1在慢性肾脏疾病中激活的基础，重点是其作用 细胞内磷酸盐耗竭和胰岛素抵抗。如果我们确定AMPD1的激活是导致 并表明它是由胰岛素抵抗、细胞内磷酸盐耗竭和尿酸引起的 一代，我们不仅将确定导致慢性肾脏疾病严重并发症的机制，而且 也是一种预防和治疗干预的潜在方法。这样的发现将是伟大的 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 卫生署。