The Musculoskeletal Cost of Organ Repair

器官修复的肌肉骨骼成本

• 批准号: 10569038
• 负责人: LEONIDAS G. KONIARIS
• 金额: $ 38.45万
• 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/10569038
• 关键词: Abdomen; Acute; Address; Adrenal Cortex Hormones; Adrenergic Agents; Amino Acids; 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; Metabolic; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle; Muscular Atrophy; Musculoskeletal; Natural regeneration; Nutritional; Operative Surgical Procedures; Organ; Organ Model; Pathologic; Pathway interactions; Patients; 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; pharmacologic; 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.

在严重损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 几天到几周这种催化剂的定义是“现有分子分解成更小的单元， 氧化以释放能量或用于其他合成代谢反应”（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损失，并随着恢复而消退。 Cuthbertson最初在1930年报道了长骨骨折患者肌肉的快速丧失， “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”。罗兹和其他人的研究发现，这种分解代谢反应，而不是营养摄入， 严重损伤后组织的修复和再生（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比例，支持持续的能量需求， 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 包括严重创伤、肝切除和烧伤在内的损伤可能需要数天至数周的分解代谢反应， 完全恢复。虽然优化术前营养可以改善手术结果，但不能防止肌肉萎缩， 猫相反，分解代谢反应受损与发病率和死亡率增加相关。 虽然目前的文献集中在病理持续性的分解代谢反应和能量 损伤后，特别是烧伤后，急性catalysts是必不可少的生存伤害。到 迄今为止，很少有研究涉及严重损伤的恢复如何诱导代谢底物的释放 以满足受损器官修复和再生的迫切需要。 我们的数据表明，受损器官的修复是以骨骼肌质量为代价的。此外，我们发现， 组织修复部分通过肝脏机制激活肌肉的catalysis。理解我们如何 在这个过程中，肌肉串扰的作用将为受伤后的治疗开辟新的范例。 重伤我们推测，损伤后肌肉的caterase是：1）关键的全身反应所需的 为受损器官的修复提供基质，2）严重损伤后的通用性，包括两者 控制（手术）和创伤性损伤，3）分子上类似于癌症中恶病质的肌肉萎缩， 其他疾病，包括由受损器官介导的萎缩因子如MuRF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）定义肝脏生长中器官串扰的机制 2）通过IL-6/雅普/TAZ通路确定器官串扰的机制， 研究雅普/TAZ调制的治疗潜力， 从损伤中恢复; 3）询问从损伤中恢复的血液和肌肉中的IL-6/雅普/TAZ通路。 需要延迟腹部闭合的主要肝切除术或严重损伤患者。