Volumetric muscle loss (VML) resulting from extremity trauma presents functional deficits and fibrosis, ultimately manifesting disability. The extensive fibrotic accumulation is expected to interfere with neural, trophic, vascular, and mechanical connectivity of any possible regenerative medicine approaches. Our objective was to quantify the muscle properties and stiffness following injury and investigate if the fibrotic deposition could be mitigated using an antifibrotic agent; we hypothesized that antifibrotic treatment would prevent the overwhelming fibrotic response. Yorkshire Cross pigs (n = 10) were randomized to sham or a nontreated ∼20% VML injury. Immediately following surgery, injured animals were further randomized to nintedanib (Ofev; 300 mg/day) or no treatment for 30 days. Longitudinal analysis of muscle function via peroneal nerve stimulation, compartment volume, and quantitative muscle stiffness using shearwave elastography were conducted. Terminally comprehensive histopathologic, biochemical, and genetic investigations were conducted on the skeletal muscle and fibrosis. Through 4 weeks post-VML, nontreated muscles presented a significant deficit (23%) in maximal torque compared to the sham operated (p < 0.01). The stiffness in the VML defect area increased significantly (7-fold) in the VML-nontreated leg than the VML antifibrotic-treated legs by 4 weeks postinjury, which was coupled with the nontreated muscle having ∼40% more hydroxyproline per mg of tissue than those receiving antifibrotic treatment (p = 0.01). This work indicates that VML injury progressively induces fibrosis and muscle stiffness. Antifibrotic treatment can mitigate the pathologic development of fibrosis. Future work should evaluate optimal timing and duration of treatments combined with regenerative medicine approaches in efforts to improve function.

中文翻译：

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猪体积性肌肉丢失损伤模型中纤维化的药理学缓解作用。

由四肢创伤引起的体积性肌肉丢失（VML）表现出功能缺陷和纤维化，最终表现为残疾。广泛的纤维化积聚预计会干扰任何可能的再生医学方法的神经，营养，血管和机械连接性。我们的目标是量化损伤后的肌肉特性和僵硬程度，并研究是否可以使用抗纤维化剂缓解纤维化沉积。我们假设抗纤维化治疗将防止压倒性纤维化反应。约克郡跨猪（n = 10）被随机分为假手术或未经治疗的约20％VML损伤。手术后立即将受伤的动物进一步随机分配给nintedanib（Ofev; 300 mg / day）或不治疗30天。进行了纵向神经分析，通过腓骨神经刺激，隔室容积和使用剪切波弹性成像的定量肌肉僵硬度。最后对骨骼肌和纤维化进行了全面的组织病理学，生化和基因研究。VML术后4周，与假手术组相比，未经处理的肌肉的最大扭矩明显不足（23％）（p <0.01）。到受伤后4周，未经VML处理的腿的VML缺损区域的硬度比经VML抗纤维化处理的腿明显增加（7倍），这与未经处理的肌肉每毫克组织的羟脯氨酸含量相比多出40％接受抗纤维化治疗的患者（p  = 0.01）。这项工作表明VML损伤逐渐引起纤维化和肌肉僵硬。抗纤维化治疗可以减轻纤维化的病理发展。未来的工作应结合再生医学方法评估最佳治疗时机和持续时间，以改善功能。