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

• 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
• 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

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.

项目摘要 骨骼肌萎缩和肌肉浪费与急性和慢性病理状况有关 例如创伤性脊髓损伤和住院床。萎缩的肌肉质量减少 与其他合并症的权力结果相关，并增加了对肥胖和糖尿病的敏感性。 当前增加肌肉质量的药物干预措施的有效性受到限制。这个穷人 功效部分是由于对有助于减少肌肉的不同机制的理解有限 大量的。线粒体功能障碍已被提出为骨骼肌萎缩的贡献者之一。 但是，有助于线粒体功能和发展的确切机制 骨骼肌萎缩尚不清楚。线粒体动力学已经成为两者的关键调节剂 骨骼肌的生理学和病理学。我们最近报告说诱发的成年骨骼肌 丝线1和2的删除对运动能力有深远的影响。此外，初步分析 这些动物表现出肌肉质量降低和诱导展开蛋白质反应的迹象 （UPR）和萎缩基因。我们还观察到骨骼肌和循环中FGF21水平升高。这些 数据表明，成年骨骼肌线粒体功能障碍和肌肉衍生的FGF21升高 有助于肌肉萎缩的发展。此外，利用脊髓损伤（SCI）模型， 发展为病理骨骼肌萎缩，我们观察到骨骼肌FGF21 mRNA的水平升高。我们 假设观察到的骨骼肌在循环中衍生出的FGF21进一步有助于 观察到萎缩。因此，该提议的总体目标是了解 骨骼肌的线粒体功能障碍，骨骼肌萎缩的发育。使用遗传 模型和可翻译的治疗干预措施，我们将尝试解决这个非常重要的问题。结果 根据这一提议，我们对有助于分子变化的理解具有广泛的意义 骨骼肌萎缩的发展。具体目的是：1。）确定FGF21的要求 骨骼肌肉萎缩的信号转导肌肉线粒体功能障碍； 2.）揭示 FGF21升高在骨骼肌肉萎缩的发展中的贡献。 绳索损伤（SCI）； 3.）确定脊髓损伤后FGF21信号的药理抑制是否 （SCI）防止骨骼肌萎缩。该提议将为我们的急需见解提供急需的见解 了解骨骼肌萎缩的分子发病机理。