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）是一种致残性疾病，影响着25%的老年人口，甚至是老年人