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.

翻译后摘要：前交叉韧带（ACL）重建是第6最常见的骨科手术 在美国进行，每年进行超过130，000次ACL重建。虽然ACL 重建通常被认为是成功的，许多患者不能恢复到损伤前的功能水平（骨骼 肌肉），并且该手术似乎对预防骨关节炎（OA）无效。这些肌肉 力量不足与肌肉生理学和结构的变化有关，包括萎缩、浸润 衰老细胞的减少，肌肉祖细胞（MPC）的减少和纤维化组织的发展， 成纤维-成脂祖细胞（FAP）的活化。事实上，衰老细胞的积累/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。我们相信衰老 在ACL损伤/手术后也会发生细胞积聚，从而干扰肌肉恢复。因此，新的生物 可能需要进行干预，以补充传统的康复方法， 解决肌肉组织病理学问题，并在ACL损伤/手术后完全恢复肌肉功能。本实验室 研究了多种生物学策略，用于改善各种损伤，疾病和 衰老我们已经表明，促进血管生成是改善血管生成的最有效的策略之一。 受伤后的肌肉愈合。其中一种方法，肌肉特异性雌激素相关受体的过度表达 γ（ERR-γ），通过转录促进血管生成的基因程序， 血管化我们认为，这种运动模拟途径可能突出了一个新的概念，并有助于在 开发新的非侵入性康复策略，以恢复ACL损伤后的肌肉功能。在 目的1，我们将研究ACL损伤/手术后的肌肉组织病理学是否与 衰老细胞的浸润，MPC的功能缺陷和FAP的过度激活，以及ERR- γ激活可防止ACL手术后发生这些肌肉组织病理学细胞事件。在目标2中，我们将 确定肌肉无力、肌肉再生减少和血管生成之间的相关性， 纤维化的发展，并研究是否运动模仿通过ERR-γ激活通过使用我们的 转基因小鼠，可以创建抵抗肌无力，使用我们的ACL损伤模型。我们的ERRγ转基因 小鼠，经过工程改造，以提高骨骼肌血管化，将是一个强大的新工具，研究 肌肉血管化、肌肉/纤维化祖细胞、衰老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广泛的肌肉功能障碍的不良结局的主要因素。 肌肉骨骼疾病，包括关节置换术和肩袖撕裂以及膝关节损伤。 用于刺激血管生成和/或减少衰老细胞的药理学方法（目前使用 可用的衰老清除药物）具有改善ACL术后许多患者结局的巨大潜力 受伤/手术，单独的物理治疗无法恢复受伤前的肌肉功能。