The Musculoskeletal Cost of Organ Repair

器官修复的肌肉骨骼成本

• 批准号: 10875228
• 负责人: LEONIDAS G. KONIARIS
• 金额: $ 11.25万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10875228
• 关键词: Musculoskeletal; Cost; Organ; Repair

Surviving critical injury or surgery requires an essential catabolic recovery period that typically extends from days to weeks. This catabolism, defined as “the breakdown of existing molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions” (Royal Chemical Society), is systemic, activates rapid loss of skeletal muscle during the period of organ repair and regeneration, and resolves with recovery. Cuthbertson originally reported the rapid loss of muscle in long-bone fracture patients in 1930, first terming it “ebb and flow”. This process has subsequently been termed “hypermetabolism” or “the adrenergic-corticoid phase”. Work by Rhoads and others found that this catabolic response, rather than nutritional intake, drives repair and regeneration of tissues following critical injury (including elective surgery). In contrast to starvation, the post-injury catabolic response is proportional to the degree of injury, supports ongoing energy needs, and supplies critical substrates (amino acids, fats) to repair, and regenerate injured organs and tissues. Serious injuries including major trauma, liver resection, and burns can require catabolic responses over days to weeks to fully recover. Although optimizing preoperative nutrition improves surgical outcomes, it does not prevent muscle catabolism. Conversely, an impaired catabolic response is associated with increased morbidity and mortality. Although current literature has focused on pathological persistence of the catabolic response and energy expenditure following injury, particularly after burns, acute catabolism is essential to survive injury. To date, little work has addressed how the recovery from critical injury induces the release of metabolic substrates from muscle and other stores to meet the acute requirement for the repair and regeneration of damaged organs. Our data indicate that injured organs are repaired at the expense of skeletal muscle mass. Furthermore, we found that tissue repair activates the catabolism of muscle partly through a liver mechanism. Understanding how we heal following injury, and the role of muscle crosstalk in this process will open new paradigms for therapies after critical injury. We hypothesize that post-injury catabolism of muscle is: 1) the critical systemic response needed to supply substrates for the repair of damaged organs, 2) universal after critical injury, including both controlled (surgery) and traumatic injury, 3) molecularly similar to muscle wasting of cachexia in cancer and other disorders, including in activation of atrogenes like MuRF1, 4) mediated by the injured organs through reciprocal, feed-forward Interleukin-6 (IL-6)/JAK/STAT to YAP/TAZ signaling, and 5) amenable to pharmacologic interventions. Here we will 1) Define mechanisms of organ crosstalk in liver growth and muscle wasting; 2) Define mechanisms of organ crosstalk via the IL-6/YAP/TAZ pathway in serious burn injury and investigate the therapeutic potential of YAP/TAZ modulation to augment recovery from injury; 3) Interrogate the IL-6/YAP/TAZ pathway in blood and muscle from patients with major liver resection or critical injury requiring delayed abdominal closure.

幸存的关键伤害或手术需要一个必需的分解代谢恢复期，通常从 几天到几周。这种分解代谢定义为“现有分子分解为较小单位的分解代谢 被氧化以释放能量或在其他合成代谢反应中使用”（皇家化学学会），是全身性的，激活 在器官修复和再生期间，骨骼肌的快速丧失，并随着恢复而解决。 Cuthbertson最初报道了1930年长骨骨折患者的肌肉迅速丧失，首先称 “潮起潮落”。此过程随后被称为“超代谢”或“肾上腺素类皮质激素 阶段”。rhoads和其他人的工作发现这种分解代谢反应而不是营养摄入量可以驱动 严重受伤后组织的修复和再生（包括选修手术）。与饥饿相反， 伤害后的分解代谢反应与伤害程度，支持持续的能源需求和 供应临界底物（氨基酸，脂肪）来修复和再生受伤的器官和组织。严肃的 包括重大创伤，肝切除和烧伤在内的伤害可能需要在数天到数周内的分解代谢反应到 尽管优化术前营养可以改善手术结果，但并不能阻止肌肉 分解代谢。相反，分解代谢反应受损与发病率和死亡率增加有关。 尽管目前的文献集中于分解代谢反应和能量的病理持久性 受伤后的支出，尤其是在烧伤后，急性分解代谢对于生存受伤至关重要。到 日期，很少的工作已经解决了从严重损伤中恢复如何引起代谢底物的释放 从肌肉和其他商店中满足受损器官修复和再生的急性需求。 我们的数据表明，受伤的器官以骨骼肌肉质量为代价进行修复。此外，我们发现 该组织修复通过肝机制部分激活肌肉的分解代谢。了解我们的方式 受伤后治愈，肌肉串扰在此过程中的作用将为治疗范围开放 严重伤害。我们假设伤害后的肌肉分解代谢是：1）所需的关键全身反应 为维修受损器官的维修提供底物，2）重伤后普遍存在，包括 受控（手术）和创伤性损伤，3）分子类似于癌症中恶病质的肌肉和 其他疾病，包括在激活诸如Murf1之类的催化性疾病中，4）受伤器官通过 倒，馈送白介素-6（IL-6）/jak/stat to yap/taz信号，5） 药理学干预措施。在这里我们将1）定义器官串扰的机制 和肌肉浪费； 2）通过IL-6/yap/taz途径定义器官串扰的机制 严重的烧伤并研究YAP/TAZ调制的治疗潜力以增加 受伤恢复； 3）从血液和肌肉中询问IL-6/YAP/TAZ途径 肝切除术或严重损伤的患者需要延迟腹部闭合。