Abstract
Regeneration of injured skeletal muscles is affected by fibrosis, which can be improved by the administration of angiotensin II (AngII) receptor (ATR) blockers in normotensive animals. However, the role of ATR in skeletal muscle fibrosis in hypertensive organisms has not been investigated yet. The tibialis anterior (TA) muscle of spontaneously hypertensive (SHR) and Wistar rats (WR) were lacerated and a lentivector encoding a microRNA targeting AngII receptor type 1 (At1) (Lv-mirAT1a) or control (Lv-mirCTL) was injected. The TA muscles were collected after 30 days to evaluate fibrosis by histology and gene expression by real-time quantitative PCR (RT-qPCR) and Western blot. SHR’s myoblasts were analyzed by RT-qPCR, 48 h after transduction. In the SHR’s TA, AT1 protein expression was 23.5-fold higher than in WR without injury, but no difference was observed in the angiotensin II receptor type 2 (AT2) protein expression. TA laceration followed by suture (LS) produced fibrosis in the SHR (23.3±8.5%) and WR (7.9±1.5%). Lv-mirAT1 treatment decreased At1 gene expression in 50% and reduced fibrosis to 7% 30 days after. RT-qPCR showed that reduction in At1 expression is due to downregulation of the At1a but not of the At1b. RT-qPCR of myoblasts from SHR transduced with Lv-mirAT1a showed downregulation of the Tgf-b1, Tgf-b2, Smad3, Col1a1, and Col3a1 genes by mirAT1a. In vivo and in vitro studies indicate that hypertension overproduces skeletal muscle fibrosis, and AngII-AT1a signaling is the main pathway of fibrosis in SHR. Moreover, muscle fibrosis can be treated specifically by in loco injection of Lv-mirAT1a without affecting other organs.
Highlights
Skeletal muscles weight about 33–40% of total body weight of non-obese men and women, being responsible for posture and voluntary movements [1]
Quantitative histological analysis of muscle fibrosis after laceration To study the relationship between hypertension and fibrosis after muscle injury, two muscle injury methods were first compared: Laceration (L) and Laceration followed by Suture (LS) (Fig 1A)
Four weeks after the L and laceration followed by suture (LS) procedures were performed in spontaneously hypertensive (SHR) and Wistar rats (WR), the muscles were isolated for analyses
Summary
Skeletal muscles weight about 33–40% of total body weight of non-obese men and women, being responsible for posture and voluntary movements [1]. Muscle injury can cause muscle contracture, atrophy, and fibrotic scar tissue, which can affect physical movements [2,3]. Skeletal muscle fibrosis of spontaneously hypertensive rat funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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