Development of biological approaches to enhance skeletal muscle rehabilitation after anterior cruciate ligament injury

开发生物学方法来增强前十字韧带损伤后骨骼肌的康复

• 批准号: 9809778
• 负责人: Johnny Huard
• 金额: $ 18.85万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-05 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9809778
• 关键词: Address; Adult; Aerobic Exercise; Age; Aging; Angiogenic Factor; Animal Model; Anterior Cruciate Ligament; Area; Atrophic; Beds; Biologic Development; Biological; Biomechanics; Blood Vessels; Cell Proliferation; Cell Respiration; Cell physiology; Cells; Collaborations; Defect; Degenerative polyarthritis; Development; Diagnostic radiologic examination; Discipline; Disease; Engineering; Event; Exercise; Exercise Tolerance; Exploratory/Developmental Grant; Extensor; Fibrosis; Functional disorder; Gene Expression Regulation; Genes; Growth Factor; Health; Histopathology; Image; Impairment; Infiltration; Injury; Intervention; Knee; Knee Injuries; Laboratories; Link; Lower Extremity; Modality; Modeling; Mus; Muscle; Muscle Weakness; Muscle function; Muscle rehabilitation; Muscular Atrophy; Muscular Dystrophies; Musculoskeletal Diseases; Natural regeneration; Nuclear Hormone Receptors; Nuclear Receptors; Operative Surgical Procedures; Orthopedic Procedures; Orthopedics; Outcome; Pathway interactions; Patients; Peripheral Vascular Diseases; Pharmaceutical Preparations; Pharmacology; Physical Exercise; Physical activity; Physical therapy; Pre-Clinical Model; Principal Investigator; Procedures; Reconstructive Surgical Procedures; Recovery; Rehabilitation therapy; Replacement Arthroplasty; Reporting; Research; Resistance; Resolution; Risk; Skeletal Muscle; Stem cells; Surgeon; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Transgenic Organisms; United States; United States National Institutes of Health; Vascularization; Work; age related; aged; angiogenesis; anterior cruciate ligament reconstruction; clinical translation; density; estrogen-related receptor; exercise intensity; gait examination; gene therapy; healing; improved; improved outcome; ligament injury; mimetics; mimicry; muscle degeneration; muscle physiology; muscle regeneration; muscle strength; muscular structure; novel; novel therapeutic intervention; overexpression; paracrine; prevent; progenitor; programs; rehabilitation strategy; repaired; rotator cuff tear; sarcopenia; senescence; stem cell therapy; tool

Abstract: Anterior cruciate ligament (ACL) reconstruction is the 6th most common orthopaedic procedure performed in the United States, with more than 130,000 ACL reconstructions performed annually. While ACL reconstruction is often considered successful, many patients do not return to pre-injury functional levels (skeletal muscle), and the procedure does not appear to be effective for preventing osteoarthritis (OA). These muscle strength deficits are associated with changes in muscle physiology and structure, including atrophy, infiltration of senescent cells, reduction in muscle progenitor cells (MPCs) and the development of fibrotic tissue through the activation of fibrogenic-adipogenic progenitor (FAPs). In fact, accumulation/infiltration of senescent cells occurs in aging-associated muscle atrophy/sarcopenia, impairing muscle function. We believe that senescent cell accumulation also occurs after ACL injury/surgery, interfering with muscle recovery. Thus, novel biological interventions may be necessary to supplement conventional rehabilitation approaches in order to specifically address muscle histopathology and fully restore muscle function after ACL injury/surgery. Our laboratory has investigated multiple biological strategies for improving muscle healing after a variety of injuries, diseases and aging. We have shown that promotion of angiogenesis is one of the most efficacious strategies to improve muscle healing after injury. One such approach, muscle-specific over-expression of estrogen-related receptor gamma (ERR-γ), recapitulates exercise by transcribing a pro-angiogenic gene program that increases muscle vascularization. We posit that this exercise-mimetic pathway may highlight a new concept and help in the development of novel, non-invasive rehabilitation strategies for restoring muscle function after ACL injury. In Aim 1, we will investigate whether muscle histopathology after ACL injury/surgery is associated with the infiltration of senescent cells, a functional defect in MPCs and over-activation of FAPs, as well as whether ERR- γ activation prevents these muscle histopathological cellular events after ACL surgeries. In Aim 2, we will determine correlations between muscle weakness, reduction in muscle regeneration and angiogenesis, and the development of fibrosis, and investigate whether exercise mimicry via ERR-γ activation via the use of our transgenic mice, can create resistance to muscle weakness, using our ACL injury model. Our ERRγ transgenic mice, engineered to enhance skeletal muscle vascularization, will be a powerful new tool for investigating the link between muscle vascularity, muscle/fibrotic progenitor cells, senescent cells, and muscle weakness after ACL injury. Muscle atrophy and degeneration are major contributors to poor outcomes for a wide range of musculoskeletal disorders, including joint replacement and rotator cuff tears as well as knee injuries. Pharmacological approaches for stimulating angiogenesis and/or reducing senescent cells (using currently available senolytic drugs) have tremendous potential to improve outcomes in many patients after ACL injury/surgery for whom physical therapy alone fails to restore pre-injury muscle function.

摘要：前交叉韧带（ACL）重建是第六个最常见的骨科手术 在美国进行，每年进行130,000多次ACL重建。而ACL 重建通常被认为是成功的，许多患者没有返回受伤前功能水平（骨骼） 肌肉），并且该过程似乎对预防骨关节炎（OA）没有有效。这些肌肉 强度定义与肌肉生理和结构的变化有关，包括萎缩，浸润 感觉细胞，肌肉祖细胞的减少（MPC）以及通过 纤维化 - 辅助祖细胞（FAP）的激活。实际上，感觉细胞的积累/浸润 发生在与衰老相关的肌肉萎缩/肌肉减少症中，损害肌肉功能。我们相信感觉 ACL损伤/手术后也会发生细胞积累，干扰肌肉恢复。那是新颖的生物学 为了补充常规康复方法，可能需要采取干预措施 解决ACL损伤/手术后的肌肉组织病理学和完全恢复肌肉功能。我们的实验室有 研究了多种生物学策略，用于改善各种损伤，疾病和 老化。我们已经表明，促进血管生成是改进的最有效策略之一。 受伤后肌肉愈合。一种这样的方法，与雌激素相关的接收器的肌肉特异性过表达 伽玛（ERR-γ），通过转录促血管生成基因程序来概括运动，以增加肌肉 血管化。我们肯定的是，这种锻炼模拟途径可能会突出一个新概念，并有助于 开发新型的无创康复策略，用于恢复ACL损伤后肌肉功能。在 AIM 1，我们将研究ACL损伤/手术后的肌肉组织病理学是否与 感觉细胞的渗透，MPC中的功能缺陷和FAP的过度激活，以及是否异常 γ激活阻止了ACL手术后这些肌肉组织病理学细胞事件。在AIM 2中，我们将 确定肌肉无力，减少肌肉再生和血管生成之间的相关性以及 开发纤维化，并研究是否通过使用我们的ERR-γ激活进行模仿 转基因小鼠可以使用我们的ACL损伤模型对肌肉无力产生抗性。我们的ERRγ转基因 旨在增强骨骼肌血管化的小鼠将成为研究该工具的强大新工具 肌肉血管，肌肉/纤维化祖细胞，感觉细胞和肌肉无力之间的联系 ACL损伤。肌肉萎缩和变性是导致不良结果的主要贡献者 肌肉骨骼疾病，包括关节置换和肩袖撕裂以及膝盖受伤。 刺激血管生成和/或减少感觉细胞的药理方法（使用当前 ACL后，可用的塞溶液药物具有巨大的潜力来改善许多患者的预后 单独物理治疗无法恢复受伤前肌肉功能的伤害/手术。