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 前十字韧带 (ACL) 损伤是一种常见的骨科损伤，可导致股四头肌持续性损伤 无力会导致患者预后不佳并增加创伤后骨关节炎 (PTOA) 的风险。 尽管进行了广泛的康复治疗，并且无论是否通过手术重建 ACL，但只有五分之一的人 患者的股四头肌力量恢复到可接受的水平。由于 ACL 损伤导致立即关闭 神经信号传导，神经肌肉电刺激（NMES）通常用于激活抑制 运动神经元，从而改善股四头肌的激活并允许力量恢复。虽然 NMES 是 广泛使用，我们自己的荟萃分析和其他数据表明临床成功不一致，可能是由于 刺激强度以及受伤后开始治疗的时间存在巨大差异。研究表明 提高我们对这种治疗的最佳强度和时机的理解，以最大限度地提高其有效性 将立即产生影响。我们新的突破性数据凸显了一种重要但被忽视的关系 神经激活丧失和线粒体功能障碍是肌肉缺陷的重要原因 ACL 损伤后。神经抑制，即动作电位的丧失，会破坏突触后钙信号传导 触发线粒体产生过量的活性氧，已知会严重损害肌肉 健康。这些数据强化了我们优化 NMES 的理由，因为这种疗法可以直接去极化抑制 在没有意志神经激活的情况下运动神经元维持肌肉的电特性 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 忠实复制临床损伤的非侵入性大鼠模型。本提案的目的是利用此 用于测试特定 NMES 治疗参数和潜在作用机制的临床前模型。目标1 将定义治疗开始的强度和时间，以最大化积极的肌肉结果，使用 定制的啮齿动物测力计，可将刺激强度和力量结果转化为 人类状况。目标 2 将测试优化的 NMES 通过减少 ACL 损伤后发生 PTOA 的危险因素。目标 3 将确定神经元丧失之间的临床重要性 激活和线粒体功能障碍，并探讨未来的临床应用是否应考虑 ACL 损伤后同时使用线粒体靶向抗氧化疗法。由于 NMES 是 ACL 损伤的护理标准，这项工作将为指导临床实践提供基础知识。