Myostatin Family Signaling in Burn-Injury Related Muscle Wasting

描述(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，以保护器官功能和提高存活率。然而，恢复期的持续性恶病质本身就是病理性的。烧伤后骨骼肌群的高代谢和分解代谢长达两年，使患者容易受到伤害和感染，阻碍伤口愈合，降低整体功能和生活质量。Myostatin是转化生长因子-2超家族中骨骼肌特异的成员，是一种有效的紧张性肌肉生长抑制因子。我们的长期目标是确定介导烧伤后肌肉萎缩的关键调控途径，以开发治疗药物。这项应用的目的是确定肌肉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，Myostatin及其相关配体促进了烧伤后肌肉的萎缩，烧伤后改变myostatin家族信号将改变烧伤后的存活率、肌肉质量和功能。在烧伤后的急性时期，肌肉抑制素信号和肌肉萎缩可能有助于生存。从长远来看，肌肉抑制素的作用和肌肉萎缩变得不适应，降低了功能，增加了脆弱性。我们基于相当多的初步数据提出了这一假设。我们开发了一种烧伤小鼠模型，尽管有过度吞噬，但仍会导致长期的炎症和分解代谢。烧伤后骨骼肌中的肌肉生长抑制素家族信号增强。矛盾的是，肌肉生长抑素缺失的小鼠表现出更强的消瘦能力，但也增加了烧伤后的存活率。应用肌肉生长抑制素可减少烧伤后的肌肉损失。然而，使用显性负ACVR2B转基因取消所有肌肉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，肌肉抑制素家族信号在烧伤后肌肉大小的控制中发挥着重要的、时间上的调节作用。为了研究烧伤中的肌肉抑制素，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，联合调查人员是肌肉抑制素研究的世界领先者，是一位非常有成就的学术外科医生和科学家，也是美国最大和最繁忙的烧伤中心之一的主任。每一项都是将这些发现最终转化为治疗学所必需的。我们将共同确定myostatin和myostatin相关配体活性在烧伤所致肌肉萎缩中的作用；确定myostatin家族受体ACVR2和ACVR2B在烧伤所致肌肉萎缩中的作用；以及确定Smad2活性在烧伤所致肌肉萎缩中的作用。 与公共健康相关：这些研究将导致对肌肉抑制素和相关配体在正常生理和烧伤消耗中调节肌肉质量的分子途径有新的见解。这些都是必要的临床前研究，以确定调节肌肉生长抑素在提高烧伤后存活率和功能方面的潜在临床益处。

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.