The Musculoskeletal Cost of Organ Repair

器官修复的肌肉骨骼成本

• 批准号: 10393304
• 负责人: LEONIDAS G. KONIARIS
• 金额: $ 0.96万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 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/10393304
• 关键词: Abdomen; Acute; Address; Adrenal Cortex Hormones; Adrenergic Agents; Amino Acids; Blood; Burn injury; Cachexia; Catabolism; Cell physiology; Chemicals; Communication; Data; Disease; Eating; Energy Metabolism; Excision; Fatty acid glycerol esters; Fracture; Growth; Impairment; Injury; Intake; Interleukin-6; Intervention; Literature; Liver; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolic; Molecular; Morbidity - disease rate; Muscle; Muscular Atrophy; Musculoskeletal; Natural regeneration; Nutritional; Operative Surgical Procedures; Organ; Oxides; Pathologic; Pathway interactions; Patients; Pharmacology; Phase; Process; Reaction; Recovery; Reporting; Role; Signal Transduction; Skeletal Muscle; Societies; Starvation; Therapeutic; Time; Tissues; Trauma; Traumatic injury; Work; cost; healing; improved; injury recovery; long bone; mortality; muscle form; nutrition; organ injury; repaired; response; severe burns; severe injury; skeletal muscle wasting; surgery outcome; tissue regeneration; tissue repair

Project Abstract (R01GM137656) 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.

项目摘要（R 01 GM 137656） 在严重受伤或手术中幸存需要一个重要的分解代谢恢复期，通常 从几天到几周。这种催化剂，定义为“现有分子分解成 被氧化以释放能量或用于其它合成代谢反应的较小单位”（皇家 化学学会），是全身性的，在器官衰竭期间激活骨骼肌的快速损失。 修复和再生，并解决与恢复。Cuthbertson最初报告说， 1930年，在长骨骨折患者的肌肉中，首次将其称为“潮起潮落”。这一进程 随后被称为“高代谢”或“肾上腺素能-皮质激素期”。Rhoads的作品 其他人发现，这种分解代谢反应，而不是营养摄入，驱动修复， 严重损伤后的组织再生（包括择期手术）。与饥饿相比， 损伤后分解代谢反应与损伤程度成正比，支持持续的能量 需要，并提供关键底物（氨基酸，脂肪），以修复和再生受损器官 和纸巾。严重的损伤，包括严重创伤、肝切除和烧伤，可能需要分解代谢 几天到几周的反应，以完全恢复。尽管优化术前营养可以改善 手术结果，它并不能防止肌肉痉挛。相反，受损的分解代谢 反应与发病率和死亡率的增加有关。虽然目前的文献集中在 损伤后分解代谢反应和能量消耗的病理持续性， 特别是在烧伤后，急性catalysts是必不可少的生存伤害。迄今为止， 阐述了严重损伤后的恢复如何诱导代谢底物的释放 从肌肉和其他商店，以满足急性需要的修复和再生 受损器官我们的数据表明，受损器官的修复是以骨骼肌为代价的 马萨诸塞州此外，我们发现，组织修复激活肌肉的catalytic部分通过一个 肝脏机制了解我们如何在受伤后愈合，以及肌肉串扰在其中的作用 这一过程将为严重损伤后的治疗开辟新的范例。我们假设受伤后 肌肉的收缩是：1）关键的全身反应，需要提供基质的修复 器官受损，2）严重损伤后普遍存在，包括控制性（手术）和创伤性 损伤，3）在分子上类似于癌症和其他疾病中恶病质的肌肉萎缩，包括在 损伤器官介导的萎缩因子（如MuRF 1，4）的激活， 相互的、前馈的白细胞介素-6（IL-6）/JAK/STAT到雅普/TAZ信号传导，以及5）服从 药物干预。在这里，我们将1）定义肝脏中器官串扰的机制 生长和肌肉萎缩; 2）通过IL-6/雅普/TAZ定义器官串扰的机制 探讨雅普/TAZ治疗严重烧伤的可能性 3）研究血液中IL-6/雅普/TAZ通路 和肌肉的患者，主要肝切除术或严重损伤，需要延迟 腹部缝合