The Musculoskeletal Cost of Organ Repair

器官修复的肌肉骨骼成本

• 批准号: 10349585
• 负责人: LEONIDAS G. KONIARIS
• 金额: $ 31.19万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349585
• 关键词: Abdomen; Acute; Address; Adrenal Cortex Hormones; Adrenergic Agents; Amino Acids; Attenuated; Biological Assay; Blood; Burn injury; Cachexia; Catabolism; Cell physiology; Chemicals; Communication; Data; Disease; Eating; Energy Metabolism; Excision; Fatty acid glycerol esters; Fracture; Gene Expression; Growth; Hepatic; Hepatomegaly; Hepatosplenomegaly; Impairment; Injury; Intake; Interleukin-6; Intervention; Knock-out; Literature; Liver; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle; Muscular Atrophy; Musculoskeletal; Natural regeneration; Nutritional; Operative Surgical Procedures; Organ; Organ Model; Oxides; Pathologic; Pathway interactions; Patients; Pharmacology; Phase; Process; Production; Reaction; Recovery; Reporting; Role; Signal Transduction; Skeletal Muscle; Skin repair; Societies; Starvation; Surgical Injuries; Testing; Therapeutic; Time; Tissues; Trauma; Traumatic injury; Work; cost; cytokine; healing; improved; injury recovery; liver cell proliferation; long bone; mortality; muscle form; nutrition; organ injury; organ regeneration; organ repair; repaired; response; severe burns; severe injury; skeletal muscle wasting; skin regeneration; surgery outcome; tissue regeneration; tissue repair; wasting

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.

在重伤或手术中幸存下来需要一个基本的分解代谢恢复期，通常从 几天到几周。这种分解代谢的定义是“现有分子分解成更小的单位，这些单位或者 氧化以释放能量或用于其他合成代谢反应“(皇家化学会)，是系统的，激活的 在器官修复和再生期间，骨骼肌迅速丧失，并随着恢复而消失。 Cuthbertson最初在1930年报道了长骨骨折患者肌肉的快速丧失，并首次将其命名为 “潮起潮落”。这一过程后来被称为“高代谢”或“肾上腺皮质激素”。 阶段“。Rhoads和其他人的研究发现，这种分解代谢反应，而不是营养摄入，推动了 严重损伤后组织的修复和再生(包括择期手术)。与饥饿相反的是， 损伤后的分解代谢反应与损伤程度成正比，支持持续的能量需求，以及 提供修复和再生受损器官和组织的关键底物(氨基酸、脂肪)。严重的 包括严重创伤、肝脏切除和烧伤在内的损伤可能需要几天到几周的分解代谢反应 完全康复。尽管优化手术前营养可以改善手术结果，但它并不能预防肌肉萎缩。 分解代谢。相反，分解代谢反应受损会增加发病率和死亡率。 虽然目前的文献关注的是分解代谢反应和能量的病理性持久性 受伤后的支出，尤其是烧伤后，急性分解代谢是受伤后存活的关键。至 到目前为止，很少有工作涉及危重损伤的恢复如何诱导代谢底物的释放。 从肌肉和其他存储，以满足修复和再生受损器官的迫切需求。 我们的数据表明，受损的器官是以骨骼肌质量为代价进行修复的。此外，我们发现， 这种组织修复在一定程度上通过肝脏机制激活肌肉的分解代谢。了解我们如何 受伤后愈合，肌肉串音在这一过程中的作用将为以后的治疗打开新的范式 伤势严重。我们假设肌肉损伤后的分解代谢是：1)所需的关键全身反应 为受损器官的修复提供底物，2)在严重损伤后普遍使用，包括两者 可控(手术)和创伤，3)分子上类似于癌症和癌症中恶病质的肌肉萎缩 其他障碍，包括由受损器官通过以下途径介导的诸如MuRF1，4)等萎缩基因的激活 与YAP/TAZ信号相互作用的前馈白介素6(IL-6)/JAK/STAT，以及5)服从 药物干预。在这里，我们将1)定义肝脏生长过程中器官串扰的机制 和肌肉萎缩；2)通过IL-6/YAP/TAZ途径确定器官串扰的机制 严重烧伤后YAP/TAZ调节增强治疗潜力的研究 3)检测血液和肌肉中IL-6/YAP/TAZ信号通路。 肝大部切除或严重损伤需延迟关腹的患者。