Myostatin Alters Muscle Composition as The Result of an ACL Injury

摘要 前交叉韧带(ACL)重建手术导致股四头肌长期无力，即 与预后较差、生物力学改变和后续受伤风险增加有关。一点儿 在过去的十年中，在改善股四头肌力量和功能结果方面取得了进展。 膝关节伸肌的细胞和形态组成的改变导致虚弱 在ACL重建之后。前交叉韧带重建诱导肌肉生长抑制素的表达 肌肉生长，局部在股四头肌。除了减缓肌肉再生，肌肉生长抑制素还 通过激活肌肉内的成体细胞促进结缔组织的合成。的目标是 这项建议是为了确定损伤的韧带和四肢肌肉的有害变化的时间进程 并确定肌肉生长抑制素在ACL术后延迟性肌肉无力的病因中是不可或缺的 眼泪。目的1将评估肌肉抑制素在损伤的前交叉韧带和股四头肌中诱导的时间框架。目标2 将使用小鼠前交叉韧带损伤模型来确定肌肉内的有害变化和疗效 卵泡抑素和一种可溶形式的肌肉生长抑素受体(激活素2B受体)可减轻这些适应不良。 Aim 3中的实验将确定肌肉抑制素的竞争性抑制是否能够挽救前交叉韧带损伤- 导致骨骼肌无力。最后，目标4将定义肌肉生长抑素信号的急性诱导 受试者前交叉韧带损伤后可预测肌力下降，结缔组织浸润 和骨骼肌祖细胞的失调。肌肉生长抑素作为治疗靶点的确定 将为进一步研究缓解前交叉韧带和其他韧带损伤后的肌肉生长抑制素信号奠定基础 受伤，以改善康复努力和病人的康复。

Abstract Anterior cruciate ligament (ACL) reconstruction surgery results in protracted quadriceps weakness that is associated with poorer outcomes, altered biomechanics and heightened risk of subsequent injuries. Little progress has been made in improving quadriceps strength and functional outcomes in the past decade. Alterations in the cellular and morphological composition of the knee extensor muscles contribute to weakness following an ACL reconstruction. ACL reconstruction induces expression of myostatin, a negative regulator of muscle growth, locally within the quadriceps. In addition to mitigating muscle regrowth, myostatin also promotes connective tissue synthesis through activation of figrogenic cells within muscle. The objective of this proposal is to determine the time course of deleterious changes to the injured ligament and limb muscle and identify myostatin as integral in the etiology of protracted muscle weakness in individuals following an ACL tear. Aim 1 will evaluate the timeframe of myostatin induction within the injured ACL and quadriceps. Aim 2 will determine the deleterious changes within the muscle using a mouse model of ACL injury and the efficacy of follistatin and a soluble form of the myostatin receptor (activin 2B receptor) to mitigate these maladaptations. Experiments in aim 3 will determine if the competitive inhibition of myostatin is capable of rescuing ACL injury- induced skeletal muscle weakness. Finally, aim 4 will define if the acute induction of myostatin signaling following an ACL injury in human subjects predicts reductions in muscle strength, connective tissue infiltration and dysregulation of skeletal muscle progenitor cells. The identification of myostatin as a therapeutic target will establish the basis for further research to mitigate myostatin signaling after ACL and other ligamentous injuries to improve rehabilitative efforts and patient recovery.