Skeletal Muscle Atrophy and Dysfunction Following Total Knee Arthroplasty

项目摘要 全膝关节置换术(TKA)是目前美国最常见的择期手术，将增加 到2030年，手术频率几乎增加五倍，达到每年350万例。这种手术是最常见的 患有晚期膝骨性关节炎(OA)的老年人和它的增加主要是由这一增长解释的 人口。尽管全膝关节置换术可靠地减轻了关节疼痛，但它未能纠正客观测量的功能 残疾，部分原因是在早期、后期，下肢神经肌肉功能急剧下降。 手术期。这些缺陷永远不会完全修复，在手术后仍然存在多年，并导致 致终生残疾。尽管TKA有这些有害的影响，但基础骨骼肌 发生在手术后早期的适应定义不明确，研究也不充分，而且有 目前还没有被广泛接受的、基于证据的干预措施来应对这些变化。为了解决这一临床问题 问题，我们在这个应用程序中的目标是定义骨骼肌的结构和功能适应 在人体全身、组织、细胞、细胞器和分子水平进行TKA，以努力 确定导致功能性残疾的因素并评估神经肌肉电疗法的效用 刺激(NMES)，以对抗手术后肌肉适应在这些相同的解剖水平。基于 我们的初步数据，我们提出了一个假设模型，在该模型中，TKA未能补救身体残疾 患者，部分原因是深层次的骨骼肌肌丝和线粒体丢失以及 在手术后的早期发展的功能障碍。此外，我们假设NMES将会改进 通过对抗这些早期的骨骼肌适应，TKA后的功能恢复。为了测试这个模型， 我们将评估膝关节骨性关节炎患者全膝关节置换术前和术后的骨骼肌结构和功能。 多个解剖水平，患者随机接受NMES或假对照干预 术后前5周。我们预计，我们的结果将产生开创性的、机械的知识 术后早期骨骼肌结构和功能对TKA的适应，这将是一个挑战 该领域的传统思维，为康复和药理学提供了新的靶点 干预。此外，我们的结果将为NMES用于预防 手术后骨骼结构和功能的有害适应。因此，我们的发现支持 有潜力推动基础科学知识和临床实践的目标，以改善长期的 膝关节骨性关节炎患者的足月功能和健康结局，这是老年人中残疾最严重的部分 人口。

Project Summary Total knee arthroplasty (TKA) is currently the most common elective surgery in the US and will increase in frequency nearly five-fold by 2030 to 3.5 million surgeries annually. This surgery is most prevalent among older adults with advanced knee osteoarthritis (OA) and its increase is explained primarily by growth in this population. Although TKA reliably reduces joint pain, it fails to correct objectively-measured functional disability due, in part, to dramatic declines in lower-extremity neuromuscular function during the early, post- surgical period. These deficits are never fully remediated, remaining for years after surgery and contributing to persistent disability. Despite these detrimental effects of TKA, the fundamental skeletal muscle adaptations that occur in the early, post-surgical period are poorly defined and understudied and there is currently no widely-accepted, evidence-based intervention to counter these changes. To address this clinical problem, our goals in this application are to define the skeletal muscle structural and functional adaptations following TKA at the whole body, tissue, cellular, organellar and molecular levels in humans in an effort to identify factors contributing to functional disability and to assess the utility of neuromuscular electrical stimulation (NMES) to counter post-surgical muscle adaptations at these same anatomic levels. Based on our preliminary data, we propose a hypothetical model in which TKA fails to remediate physical disability in patients, in part, because of the profound skeletal muscle myofilament and mitochondrial loss and dysfunction that develops during the early, post-surgical period. Moreover, we posit that NMES will improve functional recovery following TKA by countering these early skeletal muscle adaptations. To test this model, we will evaluate knee OA patients prior to and following TKA for skeletal muscle structure and function at multiple anatomic levels, with patients randomized to receive NMES or sham control intervention during the first 5 weeks post-surgery. We anticipate that our results will yield seminal, mechanistic knowledge of the early, post-surgical skeletal muscle structural and functional adaptations to TKA, which will challenge conventional thinking in this field and provide novel targets for rehabilitative and pharmacological intervention. Additionally, our results will provide mechanistic evidence for the utility of NMES to prevent deleterious post-surgical adaptations in skeletal structure and function. Our findings, therefore, hold the potential to advance both basic scientific knowledge and clinical practice towards the goal of improving long- term functional and health outcomes in knee OA patients, the most disabled sector of the older adult population.