HIF-1α regulation in mammalian hibernators: role of non-coding RNA in HIF-1α control during torpor in ground squirrels and bats

A potential role for non-coding RNAs, miR-106b and antisense hypoxia inducible transcription factor-1 (HIF-1α), in HIF-1α regulation during mammalian hibernation was investigated in two species, the thirteen-lined ground squirrel (Ictidomys tridecemlineatus) and the little brown bat (Myotis lucifugus). Both species showed differential regulation of HIF-1α during hibernation. HIF-1α protein levels increased significantly in skeletal muscle of both species when animals entered torpor, as well as in bat liver. HIF-1α mRNA levels correlated with the protein increase in bat skeletal muscle and liver but not in squirrel skeletal muscle. Antisense HIF-1α transcripts were identified in skeletal muscle of both hibernators. The expression of antisense HIF-1α was reduced in skeletal muscle of torpid bats compared with euthermic controls, suggesting that release of inhibition by the antisense RNA contributes to regulating HIF-1α translation in this tissue during torpor. The expression of miR-106b, a microRNA associated with HIF-1α regulation, also decreased during torpor in both skeletal muscle and liver of bats and in ground squirrel skeletal muscle. These data present the first evidence that non-coding RNA provides novel post-transcriptional mechanisms of HIF-1α regulation when hibernators descend into deep cold torpor, and also demonstrate that these mechanisms are conserved in two divergent mammalian orders (Rodentia and Chiroptera).