Losartan administration reduces fibrosis but hinders functional recovery after volumetric muscle loss injury
Losartan administration reduces fibrosis but hinders functional recovery after volumetric muscle loss injury
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DOI：
10.1152/japplphysiol.00689.2014
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发表时间：
2014-11-15
影响因子：
3.3
通讯作者：
Walters, Thomas J.
中科院分区：
文献类型：
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作者：
Garg, Koyal;Corona, Benjamin T.;Walters, Thomas J.
氯沙坦是美国食品和药物管理局批准的抗高血压药物，最近作为一种抗纤维化疗法出现。此前，氯沙坦已成功用于在多种可恢复的骨骼肌损伤（例如挫伤和撕裂）模型中减少纤维化并改善肌肉再生和功能。在这项研究中，在路易斯大鼠体积肌损失（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功效。 VML 被定义为骨骼肌的外伤或手术损失并导致功能障碍。这是导致受伤军人因病从军队退役的十大原因之一。这项研究表明，恢复几周后，VML 损伤几乎不会导致肌肉再生，但其特点是持续炎症、促纤维化标志物和细胞外基质（即 I 型胶原）的慢性上调以及缺损部位的脂肪沉积，这些都表现出无法恢复的力量产生缺陷。给予 10 mg.kg(-1).day(-1) 的氯沙坦能够调节纤维化标志物的基因表达，并且还可以有效减少受伤肌肉中的纤维化（即 I 型胶原蛋白的沉积）。然而，肌肉再生并没有改善，反而观察到对肌肉功能的有害影响。我们认为，在没有再生的情况下，纤维化的减少会恶化 VML 损伤肌肉传递力的能力，最终导致肌肉功能下降。
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.