Regulation of Human Muscle Protein Metabolism Following Burn Injury

描述(由申请人提供)：严重烧伤导致高分解代谢状态，持续长达一年，并导致骨骼肌群的戏剧性损失。加速的蛋白质丢失可能是肌肉退化和随后肌肉萎缩最快的原因。瘦体重的减少会增加患者感染的风险，并损害伤口愈合。虽然人们普遍认为烧伤会导致骨骼肌长时间的分解代谢，但其背后的分子机制尚不清楚。同样不清楚的是，为什么在患者的烧伤创面“愈合”后，骨骼肌萎缩仍然存在。为了回答这些问题，将从烧伤面积超过全身表面积20%-60%的受试者身上获取血清和肌肉样本，并将其与匹配的对照组的样本进行比较。烧伤后4-10天取材，伤情愈合后6-9个月取材。将对肌肉样本进行测试，以确定参与肌肉蛋白质合成和降解的分子信号通路的激活情况。确定哪些蛋白质合成和降解途径在恢复过程中被上调或被抑制，对于了解如何最大限度地减少烧伤后肌肉损失至关重要。为了分离烧伤环境对骨骼肌的影响，将使用体外系统。烧伤患者在康复早期和晚期的血清将用于健康的人类骨骼肌细胞。将测量肌肉生长和蛋白质代谢的各种标记物，以确定烧伤血清对健康骨骼肌的影响。从这些体外实验中获得的结果将确定炎症细胞因子等循环因素如何影响远端骨骼肌分解代谢。完成这些研究后，将对烧伤引起的肌肉萎缩有更好的了解。这项研究项目对烧伤界的科学家和医生以及对骨骼肌萎缩感兴趣的研究人员具有极高的科学影响力。必须强调的是，除非首先更好地了解导致这些患者肌肉蛋白丢失的潜在机制，否则治疗效果将无法实现。所描述的研究项目将提供重要的机制数据，预计这些数据将显著影响治疗烧伤所致人类肌肉萎缩的方法。 公共卫生相关性：在严重烧伤后的恢复过程中，全身骨骼肌急剧减少。这些研究将帮助我们了解导致肌肉丧失的分子和细胞方面。了解烧伤后肌肉丢失的控制机制将有助于开发预防它的治疗方法。

DESCRIPTION (provided by applicant): Severe burn injury leads to a hypercatabolic state that lasts for up to one year and results in the dramatic loss of skeletal muscle mass. The accelerated protein loss contributes to what is likely the most rapid rate of muscle degradation and subsequent muscle atrophy observed. The loss of lean body mass increases the patient's risk for infection and impairs wound healing. While it is well accepted that prolonged skeletal muscle catabolism occurs due to burn injuries in humans, the molecular events underlying this have yet to be elucidated. Also unknown is why skeletal muscle atrophy persists even after the patient's burn wounds have "healed." To answer these questions, serum and muscle samples will be obtained from subjects burned over 20-60% of total body surface area and compared to those from matched controls. Burn samples will be obtained four to ten days post-burn injury and again six to nine months post-burn injury after injuries have healed. Muscle samples will be tested to determine the activation of molecular signaling pathways involved in muscle protein synthesis and degradation. Determination of which protein synthesis and degradation pathways are upregulated or suppressed during the recovery process is crucial to understanding how to minimize post-burn muscle loss. To isolate the effects of the burn milieu on skeletal muscle, an in vitro system will be used. Serum from burn subjects in the early and late stages of recovery will be applied to healthy, human skeletal muscle cells. Various markers of muscle growth and protein metabolism will be measured to determine the effect of burn-serum on healthy skeletal muscle. The results obtained from these in vitro experiments will determine how circulating factors such as inflammatory cytokines affect remote skeletal muscle catabolism. After completion of these studies, a better understanding of burn-induced muscle atrophy will exist. This research project holds an extremely high degree of scientific impact for scientists and doctors within the burn community as well as researchers interested in skeletal muscle atrophy. It must be emphasized that treatment efficacy will not be achieved without first having a better understanding of the underlying mechanisms leading to muscle protein losses in these patients. The research project described will provide important mechanistic data that are expected to markedly influence the approach to treating human muscle atrophy consequent to burn injury. PUBLIC HEALTH RELEVANCE: During recovery from severe burn injury, a dramatic loss of skeletal muscle occurs throughout the body. These studies will help us understand the molecular and cellular aspects that lead to this muscle loss. Understanding the mechanisms controlling muscle loss after burn will allow for the development of treatments to prevent it.