Transcriptome remodeling and adaptive preservation of muscle protein content in hibernating black bears

Abstract

Hibernation is an energy-saving adaptation associated with physical inactivity. In contrast to most mammals, hibernating bears demonstrate limited loss of muscle mass and protein content over the prolonged periods of immobility and fasting during winter. This suggests that bears have natural adaptive mechanisms preserving muscle mass and functionality. To identify transcriptional changes that underlie molecular mechanisms attenuating muscle loss, we conducted a large-scale gene expression profiling (14,199 genes) by transcriptome sequencing in quadriceps of adult black bears, comparing hibernating animals (n=5) and summer active animals (n=5). Gene set enrichment analysis showed significant positive correlation between hibernating phenotype and expression changes of genes involved in translation, ribosome and the mTORC1 mediated signaling. In contrast, coordinated transcriptional reduction was detected for genes involved in catabolism of branched chain amino acid (BCAA) suggesting preservation of BCAA. These findings imply maintenance of protein biosynthesis through the mTORC1 signaling positively activated by availability of BCAA in muscle during hibernation. Support for this conclusion comes from overexpression of RRAGD and RRAGB, crucial regulator of the mTORC1 response to leucine availability, and up regulation of EIF4B, downstream target of the mTORC1 signaling. Consistent with the mTORC1 suppression of autophagy-dependent protein degradation, MAP1LC3A and ULK1 were down regulated in hibernating muscle. The maintenance of protein biosynthesis and decrease in protein catabolism through the mTORC1 signaling as response to BCAA availability likely contribute to the preservation of muscle protein through prolonged periods of immobility and fasting during hibernation.