Myostatin Family Signaling in Burn-Injury Related Muscle Wasting

描述（由申请人提供）：烧伤或其他危及生命的损伤后肌肉蛋白质和脂肪分解代谢可能是一种急性适应性反应，以保持器官功能和促进生存。然而，恢复期持续的恶病质本身就是病理性的。烧伤后长达2年的骨骼肌高代谢和分解代谢使患者容易受伤和感染，延缓伤口愈合，降低整体功能并降低生活质量。肌生长抑制素是转化生长因子- 2超家族的骨骼肌特异性成员，是一种有效的强直性肌肉生长抑制剂。我们的长期目标是确定烧伤后肌肉萎缩的关键调控途径，以开发治疗方法。本应用的目的是确定肌肉生长抑制素信号通路在烧伤后肌肉萎缩中的作用。我们的假设是，肌肉生长抑制素及相关配体促进烧伤后肌肉萎缩，而改变烧伤后肌肉生长抑制素家族信号将改变烧伤存活率、肌肉质量和功能。在急性烧伤后时期，肌肉生长抑制素信号和肌肉萎缩可能促进生存。从长远来看，肌肉生长抑制素的作用和肌肉萎缩变得不适应，降低功能和增加脆弱性。我们根据相当多的初步资料作出这一假设。我们建立了一个小鼠烧伤模型，引起长期的过度炎症和分解代谢，尽管嗜食。烧伤后骨骼肌肌生长抑制素家族信号增加。矛盾的是，没有肌肉生长抑制素的小鼠表现出增强的消瘦，但也增加了烧伤后的存活率。给予肌肉生长抑制素抑制剂可减少烧伤后的肌肉损失。然而，使用显性阴性ACVR2B转基因去除所有肌生成抑制素家族配体的信号会导致烧伤后100%的死亡率。这些数据表明，肌肉生长抑制素家族信号在烧伤后肌肉大小的控制中起着重要的、暂时的调节作用。为了研究烧伤中的肌肉生长抑制素，我们组建了一个高度互动的多学科团队。PI是一名分子生物学家和肌肉萎缩方面的专家，他的合作者是肌肉生长抑制素研究领域的世界领先者，是一位非常有成就的学术外科医生和科学家，也是美国最大、最繁忙的烧伤中心之一的主任。每一个都是将这些发现最终转化为治疗方法所必需的。我们将共同确定肌肉生长抑制素和肌肉生长抑制素相关配体活性在烧伤引起的肌肉萎缩中的作用；确定肌肉生长抑制素家族受体ACVR2和ACVR2B在烧伤引起的肌肉萎缩中的作用；并确定SMAD2活性在烧伤引起的肌肉萎缩中的作用。

DESCRIPTION (provided by applicant): Muscle protein and adipose catabolism after burn or other life-threatening injury is likely an acute, adaptive response to preserve organ function and promote survival. However, persistent cachexia in the convalescent phase is pathological in itself. Hypermetabolism and catabolism of skeletal muscle mass for up to 2 years after burn injury renders patients vulnerable to injury and infection, retards wound healing, reduces overall function and diminishes quality of life. Myostatin is a skeletal muscle-specific member of the Transforming Growth Factor- 2 superfamily and a potent, tonic muscle growth inhibitor .Our long term goal is to define the key regulatory pathways mediating muscle wasting after burn injury for the purpose of developing therapeutics. The objective of this application is to determine the role of the myostatin signaling pathway in muscle wasting after burn injury. Our hypothesis is that myostatin and related ligands promote muscle wasting after burn injury, and that altering myostatin family signaling after burn will change burn survival, muscle mass and function. In the acute post-burn period, myostatin signaling and muscle wasting may facilitate survival. In the longer term, myostatin action and muscle wasting becomes maladaptive, reducing function and increasing vulnerability. We base this hypothesis on considerable preliminary data. We developed a mouse model of burn injury that causes long- term hyperinflammation and catabolism despite hyperphagia. Myostatin family signaling was increased in skeletal muscle after burn. Paradoxically, myostatin null mice exhibited enhanced wasting but also increased survival after burn. Administration of a myostatin inhibitor reduced muscle loss after burn injury. However, abolishing signaling from all myostatin-family ligands using a dominant negative ACVR2B transgenic resulted in 100% mortality after burn injury. These data indicate that myostatin family signaling plays an important, temporally regulated role in muscle size control after burn-injury. To study myostatin in burn, we have assembled a highly interactive, multidisciplinary team. The PI is a molecular biologist and expert in muscle wasting and the co-investigators are the world-leader in myostatin research, a highly accomplished academic surgeon-scientist, and the director of one of the country's largest and busiest burn centers. Each is necessary for the ultimate translation of these findings to therapeutics. Together we will determine the role of myostatin and myostatin-related ligand activity in burn-induced muscle wasting; determine the role of the myostatin family receptors ACVR2 and ACVR2B in burn-induced muscle wasting; and determine the role of SMAD2 activity in burn-induced muscle wasting.