Angiotensin II Receptor Blockade Administered after Injury Improves Muscle Regeneration and Decreases Fibrosis in Normal Skeletal Muscle

Abstract

Background Several therapeutic agents have been shown to inhibit fibrosis and improve regeneration after injury in skeletal muscle by antagonizing transforming growth factor-β1. Angiotensin receptor blockers have been shown to have a similar effect on transforming growth factor-β1 in a variety of tissues. Hypothesis Systemic treatment of animals after injury of skeletal muscle with an angiotensin receptor blocker may decrease fibrosis and improve regeneration, mainly through transforming growth factor-β1 blockade, and can be used to improve skeletal muscle healing after injury. Study Design Controlled laboratory study. Methods Forty mice underwent bilateral partial gastrocnemius lacerations. Mice were assigned randomly to a control group (tap water), a low-dose angiotensin receptor blocker group (losartan, 0.05 mg/mL), or a high-dose angiotensin receptor blocker group (0.5 mg/mL). The medication was dissolved in tap water and administered enterally. Mice were sacrificed 3 or 5 weeks after injury, and the lacerated muscles were examined histologically for muscle regeneration and fibrosis. Results Compared with control mice at 3 and 5 weeks, angiotensin receptor blocker-treated mice exhibited a histologic dose-dependent improvement in muscle regeneration and a measurable reduction in fibrous tissue formation within the area of injury. Conclusion By modulating the response to local and systemic angiotensin II, angiotensin receptor blocker therapy significantly reduced fibrosis and led to an increase in the number of regenerating myofibers in acutely injured skeletal muscle. The clinical implications for this application of angiotensin receptor blockers are potentially far-reaching and include not only sports- and military-related injuries, but also diseases such as the muscular dystrophies and trauma- and surgery-related injury. Clinical Relevance Angiotensin receptor blockers may provide a safe, clinically available treatment for improving healing after skeletal muscle injury.