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，导致股四头肌永久性损伤。 虚弱导致患者预后不佳，并增加创伤后骨关节炎(PTOA)的风险。 尽管进行了广泛的康复，无论前交叉韧带是否通过手术重建，只有1/5 患者的股四头肌力量恢复到可以接受的水平。由于前交叉韧带损伤导致立即关闭 神经信号、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。尽管NMES是 广泛应用，我们自己的荟萃分析等数据显示，临床成功是不一致的，很可能是由于 在刺激强度和受伤后多快开始治疗方面存在巨大差异。研究表明 提高我们对这种治疗的最佳强度和时机的理解，以最大限度地发挥其有效性 会立即产生影响。我们新的突破性数据突出了一种重要而被忽视的关系 神经激活丧失和线粒体功能障碍是肌肉缺陷的重要因素 前交叉韧带损伤后。神经抑制，即动作电位的丧失，扰乱突触后钙信号 这会触发线粒体产生过量的活性氧，从而严重损害肌肉 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 运动神经元在没有意志性神经激活的情况下维持肌肉的电特性 是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 一种真实复制临床损伤的非侵入性大鼠模型。这项提议的目标是利用这一点 临床前模型，以测试特定的NMES治疗参数和潜在的作用机制。目标1 将定义开始治疗的强度和时间，以使用 定制的啮齿动物测功器，将刺激强度和力量结果转换为 人类的状况。目标2将测试优化的NMES通过减少 前交叉韧带损伤后PTOA的危险因素。目标3将确定神经丧失之间的临床重要性 激活和线粒体功能障碍，并探索未来的临床应用是否应该考虑 前交叉韧带损伤后同时使用线粒体靶向抗氧化剂治疗。由于NMES是 这项工作将为指导临床实践提供基础知识。