Garg Koyal, Corona Benjamin T, Walters Thomas J
US Army Institute of Surgical Research, Extremity Trauma and Regenerative Medicine, Fort Sam Houston, Texas.
US Army Institute of Surgical Research, Extremity Trauma and Regenerative Medicine, Fort Sam Houston, Texas
J Appl Physiol (1985). 2014 Nov 15;117(10):1120-31. doi: 10.1152/japplphysiol.00689.2014. Epub 2014 Sep 25.
Losartan is a Food and Drug Administration approved antihypertensive medication that is recently emerging as an antifibrotic therapy. Previously, losartan has been successfully used to reduce fibrosis and improve both muscle regeneration and function in several models of recoverable skeletal muscle injuries, such as contusion and laceration. In this study, the efficacy of losartan treatment in reducing fibrosis and improving regeneration was determined in a Lewis rat model of volumetric muscle loss (VML) injury. VML has been defined as the traumatic or surgical loss of skeletal muscle with resultant functional impairment. It is among the top 10 causes for wounded service members to be medically retired from the military. This study shows that, after several weeks of recovery, VML injury results in little to no muscle regeneration, but is marked by persistent inflammation, chronic upregulation of profibrotic markers and extracellular matrix (i.e., collagen type I), and fat deposition at the defect site, which manifest irrecoverable deficits in force production. Losartan administration at 10 mg·kg(-1)·day(-1) was able to modulate the gene expression of fibrotic markers and was also effective at reducing fibrosis (i.e., the deposition of collagen type I) in the injured muscle. However, there were no improvements in muscle regeneration, and deleterious effects on muscle function were observed instead. We propose that, in the absence of regeneration, reduction in fibrosis worsens the ability of the VML injured muscle to transmit forces, which ultimately results in decreased muscle function.
氯沙坦是一种经美国食品药品监督管理局批准的抗高血压药物，最近正作为一种抗纤维化疗法崭露头角。此前，氯沙坦已成功用于减少纤维化，并改善多种可恢复性骨骼肌损伤模型（如挫伤和撕裂伤）中的肌肉再生及功能。在本研究中，在Lewis大鼠容积性肌肉损失（VML）损伤模型中确定了氯沙坦治疗在减少纤维化和改善再生方面的疗效。VML被定义为骨骼肌的创伤性或手术性损失并导致功能受损。它是受伤军人因医疗原因从军队退役的十大原因之一。本研究表明，经过数周恢复后，VML损伤导致几乎没有肌肉再生，但其特征是持续炎症、促纤维化标志物和细胞外基质（即I型胶原蛋白）的慢性上调以及缺损部位的脂肪沉积，这些表现出力量产生方面不可恢复的缺陷。以10 mg·kg⁻¹·天⁻¹的剂量给予氯沙坦能够调节纤维化标志物的基因表达，并且在减少受损肌肉中的纤维化（即I型胶原蛋白的沉积）方面也有效。然而，肌肉再生没有改善，反而观察到对肌肉功能的有害影响。我们提出，在没有再生的情况下，纤维化的减少会使VML损伤肌肉传递力量的能力恶化，最终导致肌肉功能下降。
