Protective Effects of Sonic Hedgehog Against Ischemia/Reperfusion Injury in Mouse Skeletal Muscle via AKT/mTOR/p70S6K Signaling

Background/aims: Skeletal muscle ischemia/reperfusion (I/R) injury is a common and severe disease. Sonic Hedgehog (Shh) plays a critical role in post-natal skeletal muscle regeneration. In the present study, the role of Shh in skeletal muscle I/R injury and the mechanisms involved were investigated.

Methods: The expression of Shh, Akt/mTOR/p70S6K and Apoptosis pathway components were evaluated following tourniquet-induced skeletal muscle I/R injury. Then, mice were subjected to systemic administration of cyclopamine or one-shot treatment of a plasmid encoding the human Shh gene (phShh) to examine the effects of Shh on I/R injury. Moreover, mice were subjected to systemic administration of NVP-BEZ235 to investigate the role of the Akt/mTOR/p70S6K pathway in Shh-triggered skeletal muscle protection.

Results: We found that the levels of Shh, Akt/mTOR/p70S6K pathway components and Cleaved Caspase 3 and the Bax/Bcl2 ratio initially increased and then decreased at different time points post-I/R injury. Moreover, Shh protected skeletal muscle against I/R injury by alleviating muscle destruction, reducing interstitial fibrosis and inhibiting Apoptosis, and these protective effects were abrogated when the Akt/mTOR/p70S6K pathway was inhibited.

Conclusion: Collectively, these data suggest that Shh signaling exerts a protective role through the Akt/mTOR/p70S6K signaling pathway during skeletal muscle I/R injury. Thus, Shh signaling may be a therapeutic target for protecting skeletal muscle from I/R injury.