LAUSR

The sequence diversity of microRNAs (miRNAs) allows these potent regulators of mRNA fate to bind multiple transcripts, giving them the power to inhibit diverse cellular processes. Therefore, miRNAs may regulate metabolic rate suppression (also termed torpor), an adaptation used by capable species to reduce energy expenditure, minimize tissue damage, and prolong life. Small RNA-sequencing of brown fat from control (37 °C) and torpid (5-8 °C) ground squirrels revealed a central role for miRNAs in torpor. Unsupervised clustering analysis of all 319 conserved miRNAs showed separation of control and torpor samples, which was supported by PCA analysis. Of the 76 miRNAs that were differentially expressed, 45 were upregulated during torpor. KEGG and GO analyses suggested these miRNAs inhibit genes within the ribosome, oxidative phosphorylation, and glycolysis/gluconeogenesis pathways. Some of the most downregulated miRNAs (miR-1-3p, miR-206 and miR-133a/b) had significant Pearson correlation coefficients, suggesting these myomiRs may be co-expressed in control animals. Only 3 of the 16 enriched KEGG pathways were less targeted by miRNAs during torpor, including cytokine-cytokine receptor interactions and the coagulation and complement cascades, suggesting epigenetic or post-translation modifications may inhibit these potentially damaging processes. Alternatively, their activation could promote damage sensing, wound repair, and improve tissue homeostasis. Overall, miRNA-seq analysis of brown fat revealed a strong role for miRNAs in the downregulation of central metabolic processes necessary for MRS, and highlighted miRNAs that could be inhibited by antagomiRs to promote brown fat activity in potential obesity treatments, or that could be used to replicate torpor in non-hibernating mammals.