Skeletal Muscle Size and Function after ACL Rupture: Predictors of OA Progression

 描述(申请人提供)：本次K08临床科学家导师研究职业生涯奖申请的目的是为PI提供先进基础科学和临床研究技术方面的培训。这次培训将使他朝着他的长期目标前进，即进行独立的翻译性整形外科康复研究，以建立治疗肌肉骨骼和关节创伤的新治疗方法。在严重的膝关节创伤后，导致创伤后骨关节炎(PTOA)发生和早期进展的病理生理学因素，如前十字韧带(ACL)断裂，目前还知之甚少。一个可能使重建前交叉韧带的患者易于发生PTOA的因素是股四头肌的神经肌肉功能障碍，继发于指标损伤、随后的手术和伴随的肌肉停用所产生的联合分解代谢后遗症。与简单的废用模型相比，前交叉韧带重建后的肌肉无力和功能障碍不能通过力量训练和矫形康复完全纠正。这种持续性的肌肉无力被认为是通过降低股四头肌在步态中减轻休克的能力，并维持力量在胫股关节的正常分布，从而使患者易于患上PTOA。这些生物力学变化可导致膝关节内异常的接触应力和负荷，从而引发软骨代谢的适应，加速其退化和PTOA的发生和发展。我们的目标是通过治疗干预，针对这些神经肌肉适应不良的根本原因，在其婴儿期解决这些问题。然而，目前，肌肉中发生的促进力量丧失的特定细胞和亚细胞适应、与之相关的生物力学步态变化以及关节软骨成分的变化还没有明确的定义。这些研究旨在从三个方面解决这一认识差距：1)在分子、细胞、组织和全身水平上确定急性前交叉韧带损伤对骨骼肌功能、结构和蛋白表达的影响；2)确定由于肌肉力量丧失而导致的步态生物力学的适应性；以及3)评估胫股关节软骨中糖胺聚糖的丢失和II型胶原纤维的破坏。为了实现这些目标，我们将研究20名前交叉韧带损伤的受试者，在术前基线和6个月的随访中，对双侧骨骼肌的力量和功能以及软骨特异性磁共振进行系列评估；并在前交叉韧带重建后的6个月评估三维步态运动学。这些研究的结果将提供有关前交叉韧带损伤和随后的手术干预对骨骼肌大小和功能的影响及其与人类步态和软骨生物学改变的关系的新的机制信息，从而促进知识的发展。这些结果有可能影响临床护理，通知开发新的干预措施，特别是针对细胞和亚细胞肌肉适应，这有助于PTOA的病因学。

 DESCRIPTION (provided by applicant): The purpose of this K08 Mentored Clinical Scientist Research Career Award application is to provide the PI with training in advanced basic science and clinical research techniques. This training will progress him toward his long-term goal of performing independent translational orthopedic rehabilitation research to establish new therapeutic approaches for the treatment of musculoskeletal and joint trauma. The pathophysiological factors that contribute to the initial onset and early progression of post-traumatic osteoarthritis (PTOA) following severe knee trauma, such as anterior cruciate ligament (ACL) rupture, are poorly understood. One factor that may predispose ACL-reconstructed patients to the onset and progression of PTOA is neuromuscular dysfunction of the quadriceps, which develops secondary to the combined catabolic sequelae produced by the index injury, subsequent surgery, and accompanying muscle disuse. Contrasting what is observed with models of uncomplicated disuse, muscular weakness and dysfunctions following ACL-reconstruction are not completely remediated by strength training and orthopedic rehabilitation. This persistent muscle weakness is thought to predispose patients to PTOA by decreasing the ability of the quadriceps to attenuate shock during gait and maintain normal distribution of forces across the tibiofemoral joint. These biomechanical alterations can lead to abnormal contact stresses and loading within the knee, which provoke adaptations in cartilage metabolism that hasten its degradation and the onset and progression of PTOA. Our goal is to address these neuromuscular maladaptations in their infancy through targeting of their root causes with therapeutic interventions. At present, however, the specific cellular and sub-cellular adaptations that occur in muscle to promote strength loss, the associated biomechanical gait alterations, and changes in articular cartilage composition have not been clearly defined. The proposed studies are designed to address this knowledge gap in three specific aims: 1) to determine the effects of acute ACL injury on skeletal muscle function, structure and protein expression at the molecular, cellular, tissue and whole body levels; 2) to define adaptations in gait biomechanics that result from muscle strength loss; and 3) to evaluate the loss of glycosaminoglycan and type-II collagen fibril disruption in the tibiofemoral articular cartilage. T accomplish these goals, we will study 20 ACL-injured subjects with serial assessments of bilateral skeletal muscle strength and function as well as cartilage-specific MRI at pre-surgical baseline and 6-month follow up; and assess 3D gait kinematics at 6 months post-ACL-reconstruction. Results from these studies will advance knowledge by providing novel mechanistic information about the effect of ACL injury and subsequent surgical intervention on skeletal muscle size and function and its relationship to altered gait and cartilage biology in humans. These results have the potential to impact clinical care by informing the development of new interventions to specifically target the cellular and sub-cellular muscle adaptations that contribute to the pathoetiology of PTOA.