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的肌肉蛋白和脂肪代谢可能是一种急性适应性反应，以保护器官功能并促进生存。然而，恢复期持续性恶病质本身是病理性的。烧伤后长达2年的骨骼肌质量的高代谢和卡替使患者易于受伤和感染，延迟伤口愈合，降低整体功能并降低生活质量。肌生成抑制素是转化生长因子2（Transforming Growth Factor- 2，TGF- 2）超家族中的一个骨骼肌特异性成员，是一种强有力的肌肉生长抑制剂，我们的长期目标是明确烧伤后肌肉萎缩的关键调控通路，以开发治疗药物。本申请的目的是确定肌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，肌肉生长抑制素和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的信号转导将改变烧伤后的存活率、肌肉质量和功能。在烧伤后急性期，肌肉生长抑制素信号和肌肉萎缩可能有助于生存。从长远来看，肌肉生长抑制素的作用和肌肉萎缩变得适应不良，降低功能和增加脆弱性。我们把这个假设建立在相当多的初步数据的基础上。我们建立了一种烧伤小鼠模型，尽管过度进食，它仍会引起长期的过度炎症和catalytic反应.烧伤后骨骼肌中肌生长抑制素家族信号转导增加。奇怪的是，肌肉生长抑制素基因敲除小鼠表现出增强的消耗，但也增加了烧伤后的存活率。肌肉生长抑制素抑制剂的施用减少了烧伤后的肌肉损失。然而，使用显性阴性ACVR 2B转基因消除来自所有肌生长抑制素家族配体的信号传导导致烧伤后100%的死亡率。这些数据表明，肌肉生长抑制素家族信号转导在烧伤后肌肉大小控制中起着重要的、时间调节的作用。为了研究烧伤中的肌生长抑制素，我们组建了一个高度互动的多学科团队。PI是一位分子生物学家和肌肉萎缩专家，共同研究者是肌肉生长抑制素研究的世界领导者，一位成就卓著的学术外科医生科学家，以及该国最大和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。我们将共同确定肌生长抑制素和肌生长抑制素相关配体活性在烧伤诱导的肌肉萎缩中的作用;确定肌生长抑制素家族受体ACVR 2和ACVR 2B在烧伤诱导的肌肉萎缩中的作用;并确定SMAD 2活性在烧伤诱导的肌肉萎缩中的作用。 公共卫生相关性：这些研究将导致对肌肉生长抑制素和相关配体在正常生理学和烧伤消耗中调节肌肉质量的分子途径的新见解。它们是确定调节肌生长抑制素以增加烧伤后存活率和功能的潜在临床益处的重要临床前研究。

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. PUBLIC HEALTH RELEVANCE: The studies will result in new insights into the molecular pathways by which myostatin and related ligands regulate muscle mass in normal physiology and in burn wasting. They are essential pre-clinical studies for determining the potential clinical benefit of modulating myostatin for increasing survival and function after burn injury.