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：前交叉韧带重建术是第六种常见的骨科手术。 在美国执行，每年执行超过130,000次前交叉韧带重建。在访问控制列表中 重建通常被认为是成功的，许多患者没有恢复到损伤前的功能水平(骨骼 肌肉)，而且这一过程似乎对预防骨关节炎(OA)并不有效。这些肌肉 力量不足与肌肉生理和结构的变化有关，包括萎缩、渗透 衰老细胞、肌祖细胞(MPC)的减少和纤维组织的发展 成纤维-成脂前体细胞(FAPs)的激活。事实上，衰老细胞的积累/渗透 发生在与衰老相关的肌肉萎缩/骨质疏松症，损害肌肉功能。我们相信衰老的人 前交叉韧带损伤/手术后也会出现细胞堆积，干扰肌肉恢复。因此，新的生物 可能有必要采取干预措施来补充传统的康复方法，以便具体 解决前交叉韧带损伤/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 研究了多种生物策略在各种损伤、疾病和创伤后改善肌肉愈合 衰老。我们已经证明促进血管生成是改善的最有效的策略之一 肌肉受伤后会愈合。其中一种方法是肌肉特异性雌激素相关受体的过度表达 伽玛(ERR-γ)，通过转录促进血管生成的基因程序来增加肌肉来概括运动 血管形成。我们推测，这种模拟运动的途径可能突出了一种新的概念，并有助于 开发新的非侵入性康复策略以恢复前交叉韧带损伤后的肌肉功能。在……里面 目的1，我们将调查前交叉韧带损伤/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，以及是否错误- γ的激活可以预防前交叉韧带手术后的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，以及 纤维化的发展，并调查是否通过ERR-γ激活通过使用OUR 利用我们的前交叉韧带损伤模型，转基因小鼠可以对肌肉无力产生抵抗力。我们的ERRγ转基因 小鼠被设计成增强骨骼肌血管形成，将成为研究骨骼肌血管形成的有力新工具 肌肉血管、肌肉/纤维前体细胞、衰老细胞和肌肉无力之间的联系 前交叉韧带损伤。肌肉萎缩和退化是导致各种疾病预后不佳的主要原因 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/或减少衰老细胞的药理学方法(目前使用 现有的促衰老药物)具有巨大的潜力来改善许多前交叉韧带患者的预后 仅靠物理治疗不能恢复受伤前肌肉功能的损伤/手术。