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

ACL 断裂后骨骼肌的大小和功能：OA 进展的预测因素

• 批准号: 8967919
• 负责人: Timothy Ward Tourville
• 金额: $ 13.7万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-10 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967919
• 关键词: Acute; Address; Anterior Cruciate Ligament; Attenuated; Award; Basic Science; Bilateral; Biology; Biomechanics; Biopsy; Cartilage; Clinical; Clinical Research; Collagen Fiber; Collagen Fibril; Contralateral; Degenerative polyarthritis; Development; Disease; Evaluation; Functional disorder; GAG Gene; Gait; Gait abnormality; Glycosaminoglycans; Goals; Human; Individual; Injury; Intervention; Joints; Knee; Knee Osteoarthritis; Knee joint; Knowledge; Lead; Leg; Lower Extremity; Magnetic Resonance Imaging; Measurement; Mentors; Microfilaments; Modeling; Molecular; Motion; Motivation; Muscle; Muscle Weakness; Muscle function; Musculoskeletal; Normal Statistical Distribution; Operative Surgical Procedures; Orthopedics; Participant; Pathology; Pathway interactions; Patients; Phase; Plant Roots; Positioning Attribute; Proteins; Randomized Controlled Trials; Recruitment Activity; Rehabilitation Research; Rehabilitation therapy; Research; Research Design; Research Technics; Role; Rotation; Rupture; Scientist; Secondary to; Shock; Skeletal Muscle; Stress; Structure; Testing; Therapeutic; Therapeutic Intervention; Tissues; Training; Trauma; Work; anterior cruciate ligament reconstruction; anterior cruciate ligament rupture; articular cartilage; career; cartilage metabolism; cellular targeting; clinical care; early onset; evidence base; experience; follow-up; functional adaptation; improved; indexing; infancy; injured; joint injury; kinematics; ligament injury; muscle strength; neuromuscular; novel; novel therapeutic intervention; outcome forecast; programs; prospective; protein expression; public health relevance; quadriceps muscle; reconstruction; relating to nervous system; strength training; therapeutic target; therapy design; trial design

 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.

 描述（由申请人提供）：本 K08 指导临床科学家研究职业奖申请的目的是为 PI 提供先进基础科学和临床研究技术的培训。此次培训将帮助他实现长期目标，即进行独立的转化骨科康复研究，以建立治疗肌肉骨骼和关节创伤的新治疗方法。严重膝关节创伤（例如前十字韧带（ACL）断裂）后导致创伤后骨关节炎（PTOA）初始发病和早期进展的病理生理学因素尚不清楚。股四头肌神经肌肉功能障碍可能是 ACL 重建患者易患 PTOA 发生和进展的因素之一，股四头肌神经肌肉功能障碍是继发损伤、后续手术和伴随的肌肉废用产生的综合分解代谢后遗症的继发性疾病。与观察到的简单废用模型相比，ACL 重建后的肌肉无力和功能障碍并不能通过力量训练和骨科康复得到完全修复。这种持续性肌肉无力被认为会降低股四头肌减弱步态冲击和维持胫股关节力正常分布的能力，从而使患者易患 PTOA。这些生物力学的改变可能导致膝关节内异常的接触应力和负荷，从而引起软骨代谢的适应，从而加速其退化以及 PTOA 的发生和进展。我们的目标是通过治疗干预措施解决这些神经肌肉适应不良的根本原因。然而，目前，肌肉中发生的促进力量损失的特定细胞和亚细胞适应、相关的生物力学步态改变以及关节软骨成分的变化尚未明确定义。拟议的研究旨在通过三个具体目标来解决这一知识差距：1）确定急性 ACL 损伤在分子、细胞、组织和全身水平上对骨骼肌功能、结构和蛋白质表达的影响； 2）定义因肌肉力量损失而导致的步态生物力学适应； 3) 评估胫股关节软骨中糖胺聚糖的损失和 II 型胶原纤维的破坏。为了实现这些目标，我们将研究 20 名 ACL 损伤受试者，对双侧骨骼肌力量和功能以及术前基线和 6 个月随访时的软骨特异性 MRI 进行系列评估；并评估 ACL 重建后 6 个月的 3D 步态运动学。这些研究的结果将通过提供关于 ACL 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机制信息来增进知识。这些结果有可能影响临床护理，为新干预措施的开发提供信息，以专门针对有助于 PTOA 病理学的细胞和亚细胞肌肉适应。