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Autocrine Action of Elevated FGF-21 Contributing to Skeletal Muscle Atrophy in Response to Mitochondrial Dysfunction

FGF-21 升高的自分泌作用导致线粒体功能障碍引起的骨骼肌萎缩

基本信息

批准号：
10469480
负责人：
Glenn Cameron Rowe
金额：
$ 45.1万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10469480
关键词：
Ablation Acute Address Adult Animals Atrophic Attenuated Bed rest Biochemical Biological Blood Circulation Body Composition Cell physiology Chimeric Proteins Chronic Clinical Contusions Data Diabetes Mellitus Disease Effectiveness Exercise Exhibits Fibroblast Growth Factor Genes Genetic Genetic Models Goals Homeostasis Impairment Inpatients Intervention Lead Link Messenger RNA Metabolism Mitochondria Modeling Molecular Morbidity - disease rate Mus Muscle Muscle Development Muscle Mitochondria Muscle function Muscular Atrophy Obesity Outcome Outer Mitochondrial Membrane Oxidative Stress Pathogenesis Pathologic Pathology Patients Performance Pharmacologic Substance Pharmacology Physiological Physiology Predisposition Protein Biosynthesis Proteins Publishing Quality Control Quality of life Recovery of Function Reporting Research Signal Transduction Skeletal Development Skeletal Muscle Spinal Cord Contusions Spinal cord injury Stress Surgical Models Testing Therapeutic Intervention antagonist autocrine comorbidity exercise capacity fibroblast growth factor 21 improved insight mRNA Expression mitochondrial dysfunction mortality mouse model muscle form new therapeutic target novel overexpression preservation prevent receptor reduced muscle mass response skeletal circulation skeletal muscle wasting skeletal preservation

项目摘要

PROJECT SUMMARY Skeletal muscle atrophy and muscle wasting is associated with both acute and chronic pathological conditions such as traumatic spinal cord injury and inpatient bedrest. Decreases in muscle mass from the atrophy is associated with power outcomes to other comorbidities, and increased susceptibility to obesity and diabetes. Current pharmaceutical interventions to increase muscle mass have been limited in their effectiveness. This poor efficacy is in part due to the limited understanding of the different mechanisms that contribute to decrease muscle mass. Mitochondrial dysfunction has been proposed as one of the contributors to skeletal muscle atrophy. However, the precise mechanisms that contribute to impaired mitochondrial functionality and the development of skeletal muscle atrophy is unknown. Mitochondrial dynamics have emerged as key regulators of both physiology and pathology in skeletal muscle. We have recently reported that induced adult skeletal muscle deletion of both mitofusin 1 and 2 have a profound effect on exercise capacity. Furthermore, preliminary analysis of these animals exhibit signs of decrease muscle mass and the induction of the unfolded protein response (UPR) and atrophy genes. We also observed elevated levels of FGF21 in skeletal muscle and circulation. These data suggest that adult skeletal muscle mitochondrial dysfunction and elevated muscle-derived FGF21 contributes to the development of muscle atrophy. Furthermore, utilizing a spinal cord injury (SCI) model, which develops pathological skeletal muscle atrophy, we observe elevated levels of skeletal muscle Fgf21 mRNA. We hypothesize that the observed elevated skeletal muscle derived FGF21 in circulation further contributes to the observed atrophy. Therefore, the overall objective of this proposal is to understand the contribution of mitochondrial dysfunction in skeletal muscle to the development of skeletal muscle atrophy. Using genetic models and translatable therapeutic interventions we will attempt to address this very important question. Results from this proposal have broad implications for our understanding of the molecular changes that contribute to the development of skeletal muscle atrophy. The specific aims are to: 1.) Establish the requirement of FGF21 signaling for skeletal muscle atrophy in response to muscle mitochondrial dysfunction; 2.) Reveal the contribution of elevated FGF21 in the development of skeletal muscle atrophy in response to a contusion spinal cord injury (SCI); 3.) Determine whether pharmacologic inhibition of FGF21 signaling after spinal cord injury (SCI) prevents skeletal muscle atrophy. This proposal will to provide much needed insights into our understanding of molecular pathogenesis of skeletal muscle atrophy.

项目总结