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， 与较差的结果，改变生物力学和后续损伤的风险增加相关。小 在过去十年中，在改善股四头肌力量和功能结果方面取得了进展。 膝伸肌的细胞和形态组成的改变导致无力 前交叉韧带重建后ACL重建诱导肌生成抑制素的表达，肌生成抑制素是ACL重建的负调节因子。 四头肌的局部肌肉生长除了减轻肌肉再生，肌生长抑制素还 通过激活肌肉内的致纤维细胞促进结缔组织合成。的目标 这个建议是为了确定受伤韧带和肢体肌肉的有害变化的时间过程 并将肌生长抑制素确定为ACL术后个体中持续性肌无力病因学的组成部分 眼泪。目的1将评估损伤ACL和股四头肌内肌生长抑制素诱导的时间范围。目的2 将使用ACL损伤的小鼠模型确定肌肉内的有害变化， 卵泡抑素和肌肉生长抑制素受体（激活素2B受体）的可溶性形式，以减轻这些适应不良。 目标3中的实验将确定肌生长抑制素的竞争性抑制是否能够挽救ACL损伤。 诱发骨骼肌无力最后，目标4将定义肌生长抑制素信号传导的急性诱导是否 在人类受试者的ACL损伤后，预测肌肉力量、结缔组织浸润 和骨骼肌祖细胞的失调。肌生成抑制素作为治疗靶点的鉴定 将为进一步研究减轻ACL和其他韧带损伤后肌生长抑制素信号传导奠定基础。 以改善康复努力和患者恢复。

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.