Translational strategies for optimizing musculoskeletal recovery after ACL injury

优化 ACL 损伤后肌肉骨骼恢复的转化策略

• 批准号: 10679066
• 负责人: Lindsey K Lepley
• 金额: $ 46.62万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679066
• 关键词: Action Potentials; Aging; Anterior Cruciate Ligament; Antioxidants; Architecture; Area; Biomechanics; Botulinum Toxins; Calcium Signaling; Characteristics; Clinical; Computer software; Custom; Data; Development; Effectiveness; Etiology; Exhibits; Future; Gait; Goals; Health; Human; Immunohistochemistry; Impairment; Inflammation; Injury; Joints; Knee; Knee joint; Knowledge; Link; Measures; Meta-Analysis; Mitochondria; Modeling; Motor; Motor Neurons; Muscle; Muscle Fibers; Muscular Atrophy; Musculoskeletal; Neural Inhibition; Operative Surgical Procedures; Orthopedics; Outcome; Patient-Focused Outcomes; Patients; Physical activity; Porosity; Pre-Clinical Model; Production; Protocols documentation; Randomized; Rattus; Reactive Oxygen Species; Recovery; Rehabilitation therapy; Research; Risk; Risk Factors; Risk Reduction; Rodent; Stimulus; Structure; Testing; Thick; Time; Torque; Translating; Traumatic Arthropathy; Treatment Cost; Work; anterior cruciate ligament injury; antioxidant therapy; bone; bone health; clinical application; clinical practice; deep learning; electrical property; experimental group; experimental study; improved; limb injury; microCT; mitochondrial dysfunction; muscle strength; neural; neuromuscular stimulation; neurotransmission; novel; postsynaptic; preclinical study; preservation; primary outcome; protective effect; quadriceps muscle; respiratory; standard of care; subchondral bone; success; translational approach

PROJECT ABSTRACT Anterior cruciate ligament (ACL) injury is a common orthopedic injury that results in persistent quadriceps weakness that drives poor patient outcomes and increases the risk of post-traumatic osteoarthritis (PTOA). Despite extensive rehabilitation, and regardless of whether the ACL is surgically reconstructed, only 1 in 5 patients regain acceptable levels of quadriceps strength. As ACL injury causes an immediate shutdown of neural signaling, neuromuscular electrical stimulation (NMES) is commonly prescribed to activate inhibited motoneurons, thereby improving quadriceps activation and permitting strength recovery. Although NMES is widely used, our own meta-analysis and other data show that the clinical success is inconsistent, likely due to tremendous diversity in stimulation intensities and how soon treatments are initiated after injury. Research that improves our understanding of the optimal intensity and timing of this treatment to maximize its effectiveness would be immediately impactful. Our new breakthrough data highlight an important and overlooked relationship between the loss of neural activation and mitochondrial dysfunction as important contributors to muscle deficits after ACL injury. Neural inhibition, i.e., the loss of action potentials, disrupts post-synaptic calcium signaling that triggers mitochondria to produce excess reactive oxygen species known to severely compromise muscle health. These data reinforce our rationale to optimize NMES as this therapy can directly depolarize inhibited motoneurons in the absence of volitional neural activation to maintain the electrical properties of muscle necessary for contraction and mitochondrial health. To understand how to optimize the delivery, we developed a non-invasive rat model that faithfully replicates the clinical injury. The objective of this proposal is to use this preclinical model to test specific NMES treatment parameters and the underlying mechanisms of action. Aim 1 will define the intensity and time of treatment initiation that maximizes positive muscle outcomes using a custom-built rodent dynamometer that will translate the intensity of stimulus and strength outcomes to the human condition. Aim 2 will test the ability of optimized NMES to be protective of knee joint health by reducing risk factors for PTOA after ACL injury. Aim 3 will determine the clinical importance between the loss of neural activation and mitochondrial dysfunction, and explore whether future clinical applications should consider the concurrent use of mitochondrial-targeted antioxidant therapies after ACL injury. As NMES is part of the standard of care for ACL injury, this work will provide fundamental knowledge to guide clinical practice.

项目摘要 前交叉韧带（ACL）损伤是一种常见的骨科损伤，导致持续性股四头肌 导致患者预后不良并增加创伤后骨关节炎（PTOA）风险的弱点。 尽管进行了广泛的康复治疗，并且无论ACL是否手术重建，只有1/5的患者 患者恢复了可接受的股四头肌强度水平。由于ACL损伤导致 神经信号，神经肌肉电刺激（NMES）通常被规定激活抑制 运动神经元，从而改善股四头肌激活并允许力量恢复。虽然NME是 广泛使用，我们自己的荟萃分析和其他数据显示，临床成功是不一致的，可能是由于 刺激强度和受伤后多久开始治疗的巨大差异。的研究 提高了我们对这种治疗的最佳强度和时间的理解，以最大限度地提高其有效性 会立即产生影响。我们新的突破性数据突出了一个重要的和被忽视的关系 神经激活的丧失和线粒体功能障碍是肌肉缺陷的重要因素， ACL损伤后神经抑制，即，动作电位的丧失，破坏突触后钙信号传导， 引发线粒体产生过量的活性氧，严重损害肌肉 健康这些数据加强了我们优化NMES的理论基础，因为这种疗法可以直接抑制去甲肾上腺素， 运动神经元在缺乏意志性神经激活的情况下维持肌肉的电特性 收缩和线粒体健康所必需的。为了了解如何优化交付，我们开发了 一种非侵入性的大鼠模型，忠实地复制了临床损伤。该提案的目的是利用这一点， 临床前模型，以测试特定的NMES治疗参数和潜在的作用机制。要求1 将定义治疗开始的强度和时间，使用 定制的啮齿动物测力计，将刺激强度和强度结果转化为 人类的状况目标2将测试优化的NMES通过减少膝关节损伤来保护膝关节健康的能力。 ACL损伤后PTOA的危险因素。目的3将确定神经功能丧失与 激活和线粒体功能障碍，并探讨未来的临床应用是否应该考虑 ACL损伤后同时使用靶向抗氧化剂治疗。由于NMES是 护理标准的ACL损伤，这项工作将提供基础知识，以指导临床实践。