The adaptive response to extreme endurance exercise might involve transcriptional and translational regulation by microRNAs (miRNAs). Therefore, the objective of the present study was to perform an integrated analysis of the blood transcriptome and miRNome (using microarrays) in the horse before and after a 160 km endurance competition. A total of 2,453 differentially expressed genes and 167 differentially expressed microRNAs were identified when comparing pre-and post-ride samples. We used a

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... pergeometric test and its generalization to gain a better understanding of the biological functions regulated by the differentially expressed microRNA. In particular, 44 differentially expressed microRNAs putatively regulated a total of 351 depleted differentially expressed genes involved variously in glucose metabolism, fatty acid oxidation, mitochondrion biogenesis, and immune response pathways. In an independent validation set of animals, graphical Gaussian models confirmed that miR-21-5p, miR-181b-5p and miR-505-5p are candidate regulatory molecules for the adaptation to endurance exercise in the horse. To the best of our knowledge, the present study is the first to provide a comprehensive, integrated overview of the microRNA-mRNA co-regulation networks that may have a key role in controlling post-transcriptomic regulation during endurance exercise. The physiological and biochemical demands of endurance exercise elicit both muscle-based and systemic responses. The main adaptations to endurance exercise include improvement of mechanical, metabolic, neuromuscular and contractile functions in muscle 1 , correction of electrolyte imbalance 2 , a decrease in glycogen storage 3 and an increase in mitochondrial biogenesis in muscle tissue 4 , and the modulation of oxidative stress 5 , intestinal permeability, muscle damage, systemic inflammation and immune responses 5 . Consequently, adaptations to endurance exercise are influenced by the transcriptional and translational regulation of genes that encode the proteins controlling these processes 5 . Over the past decade, microRNAs (miRNAs) have emerged as novel elements in the rapid, reversible regulation of transcription and translation 6 . MiRNAs are small non-coding RNAs molecules (~19-24 bp in length) that are synthesized from short hairpin precursors and that reportedly degrade or inhibit the translation of their target genes by binding to the 3′ untranslated region (UTR) of coding mRNAs 7 . In fact, miRNAs molecules may regulate up to one-third of the mammalian transcriptome 8 and appear to be stable outside the cell (e.g. when incorporated into exosomes 9 , microvesicles 10 , lipoproteins 11 or Argonaute2 protein complexes 12 ).