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.
['Zeng|Qiu|Q|', 'Fu|Qining|Q|', 'Wang|Xuehu|X|', 'Zhao|Yu|Y|', 'Liu|Hong|H|', 'Li|Zhui|Z|', 'Li|Fenghe|F|']
D000818:Animals D015153:Blotting, Western D004195:Disease Models, Animal D005455:Fluorescent Antibody Technique D053823:Hedgehog Proteins D020287:In Situ Nick-End Labeling D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018482:Muscle, Skeletal D051057:Proto-Oncogene Proteins c-akt D015427:Reperfusion Injury D038762:Ribosomal Protein S6 Kinases, 70-kDa D015398:Signal Transduction D058570:TOR Serine-Threonine Kinases D014704:Veratrum Alkaloids
Sonic hedgehog Ischemia/reperfusion Skeletal muscle Apoptosis