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

项目总结 骨骼肌萎缩和肌肉萎缩与急性和慢性病理情况有关。 如创伤性脊髓损伤和住院患者卧床休息。肌肉萎缩导致的肌肉质量减少 与其他合并症的动力结果相关，并增加肥胖和糖尿病的易感性。 目前增加肌肉质量的药物干预措施的有效性有限。这个可怜的人 疗效的部分原因是对导致肌肉减少的不同机制的了解有限。 质量。线粒体功能障碍被认为是骨骼肌萎缩的原因之一。 然而，导致线粒体功能和发育受损的确切机制 骨骼肌萎缩的原因尚不清楚。线粒体动力学已成为两者的关键调节因素 骨骼肌的生理学和病理学。我们最近报道了诱导成人骨骼肌 丝裂原蛋白1和2的缺失对运动能力有深远的影响。此外，初步分析 这些动物的肌肉质量有减少的迹象，并诱导了未折叠的蛋白质反应 (UPR)和萎缩基因。我们还观察到骨骼肌和循环中FGF21水平的升高。这些 数据表明，成人骨骼肌线粒体功能障碍和肌源性FGF21升高 有助于肌肉萎缩的发展。此外，利用脊髓损伤(SCI)模型，该模型 发生病理性骨骼肌萎缩时，我们观察到骨骼肌FGF21mRNA水平升高。我们 假设观察到的循环中升高的骨骼肌源性FGF21进一步有助于 观察到萎缩。因此，这项建议的总体目标是了解 骨骼肌线粒体功能障碍可发展为骨骼肌萎缩。使用遗传 模型和可翻译的治疗干预我们将尝试解决这个非常重要的问题。结果 这一提议对我们理解分子变化具有广泛的意义，这些变化有助于 骨骼肌萎缩的发展。具体目标是：1.建立FGF21的要求 骨骼肌萎缩信号对肌肉线粒体功能障碍的反应；揭开 FGF21升高在脊髓挫伤后骨骼肌萎缩发展中的作用 脊髓损伤(SCI)；确定脊髓损伤后药物对FGF21信号的抑制作用 (SCI)可防止骨骼肌萎缩。这项提案将为我们的 对骨骼肌萎缩分子发病机制的认识。

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.