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Cellular energetics as a regulator of muscle mass and mitochondrial content during muscle atrophy

细胞能量学作为肌肉萎缩期间肌肉质量和线粒体含量的调节剂

基本信息

批准号：
9751765
负责人：
JEFFREY J BRAULT
金额：
$ 32.24万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-24 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751765
关键词：
5&apos -AMP-activated protein kinase AMP Deaminase Address Adenine Nucleotides Adult Aging Anabolism Area Atrophic Binding Bioenergetics Biogenesis Body Weight decreased Cells Cessation of life Chemicals Chronic Chronic Disease Chronic Wasting Disease Complication Data Deaminase Denervation Depressed mood Diabetes Mellitus Energy Supply Etiology FDA approved Food deprivation (experimental)Functional disorder Gene Targeting Genetic Transcription Glucocorticoids Goals Heart failure Hindlimb Impairment Lead Link Malignant Neoplasms Measurable Mediator of activation protein Messenger RNA Metabolic Metabolism Mission Mitochondria Molecular Mus Muscle Muscle Fibers Muscle Mitochondria Muscle Proteins Muscular Atrophy National Institute of Arthritis and Musculoskeletal and Skin Diseases Nerve Operative Surgical Procedures Pathology Pathway interactions Pharmacologic Substance Phosphotransferases Physiological Positioning Attribute Process Production Protein Degradation Induction Protein Isoforms Protein Kinase Proteins Proteolysis Public Health Research Role Signal Transduction Skeletal Muscle Testing Thermodynamics Time base disability falls fiber cell improved improved functioning insight knock-down multicatalytic endopeptidase complex muscle form new therapeutic target novel overexpression prevent protein activation protein complex protein degradation response skeletal muscle wasting treatment strategy

项目摘要

Project Summary Skeletal muscle atrophy is a major cause of disability and death in many chronic diseases, e.g. cancer, diabe- tes, and heart failure. Despite diverse etiology, atrophying muscles share many common features, like loss of mitochondrial content and depressed energetic state. One probable regulator of muscle mass and mitochon- dria during atrophy is the metabolic enzyme AMP deaminase (AMPD), which isoform 3 is increased up to 100- fold during atrophy. AMPD catalyzes the thermodynamically irreversible degradation of AMP and thereby also controls the size of the adenine nucleotide (ATP ↔ ADP ↔ AMP) pool. Binding or degrading AMP is particu- larly important since its free, cytosolic levels are detected by the energy sensing enzyme AMP-activated pro- tein kinase (AMPK), a well-described inducer of mitochondrial content. Thus, AMPD3 is uniquely positioned to modulate a major intracellular energetic signal, [AMP]/[ATP] ratio. To date, the molecular mechanisms that link muscle atrophy, cellular energetics, and mitochondria biogenesis are largely unknown. The long-term goal of this project is to identify new targets to increase muscle mass, mitochondrial content and perhaps improve the energetic state and function of atrophic muscle. The objective of this application is to determine whether during muscle atrophy AMPD3 decreases mitochondrial production and accelerates muscle protein loss. The central hypothesis is that high levels of AMPD3, which degrades the adenine nucleotide pool, triggers loss of mito- chondria and increases the rate of protein degradation. This is based, in part, on exciting preliminary data from cultured muscle showing that overexpression of AMPD3 mimics the energy deficit of atrophy, increases prote- olysis rate, and decreases protein content; while knockdown of AMDP3 in adult muscle protects against mus- cle weight loss of denervation atrophy. To test the central hypothesis, we propose to knockdown or remove AMPD3 in skeletal muscle fibers/cells that are non-atrophying or atrophying due to various energetic insults: either surgical denervation of one hindlimb (decreased energy demand), food deprivation (decreased energy supply), and glucocorticoid treatment (increase in demand and decrease in supply). The Aims of this proposal are to 1) To determine the role of AMP deaminase as a mediator of mitochondrial loss during skeletal muscle atrophy, and 2) determine the role of AMP deaminase as a mediator of protein loss during skeletal muscle at- rophy. The working hypotheses are that loss of AMPD3 during atrophy will increase [AMP], mitochondrial bio- genesis, and mitochondrial content. Conversely, overexpression of AMPD3, because of impairment in cellular energetics, will trigger accelerated protein degradation and muscle fiber size loss. The expected results of this proposal, demonstrating the energetic control of muscle atrophy, will not only provide novel insights into how energetics/metabolism and muscle mass are linked mechanistically, but will also be expected to reveal novel therapeutic targets to slow or stop muscle mass loss in most, if not all, atrophy conditions.

项目总结