title: Understanding the response to endurance exercise using a systems biology approach: combining blood metabolomics, transcriptomics and miRNomics in horses.
abstract: Endurance exercise in horses requires adaptive processes involving physiological, biochemical, and cognitive-behavioral responses in an attempt to regain homeostasis. We hypothesized that the identification of the relationships between blood metabolome, transcriptome, and miRNome during endurance exercise in horses could provide significant insights into the molecular response to endurance exercise. For this reason, the serum metabolome and whole-blood transcriptome and miRNome data were obtained from ten horses before and after a 160 km endurance competition.
  
  
  
  We obtained a global regulatory network based on 11 unique metabolites, 263 metabolic genes and 5 miRNAs whose expression was significantly altered at T1 (post- endurance competition) relative to T0 (baseline, pre-endurance competition). This network provided new insights into the cross talk between the distinct molecular pathways (e.g. energy and oxygen sensing, oxidative stress, and inflammation) that were not detectable when analyzing single metabolites or transcripts alone. Single metabolites and transcripts were carrying out multiple roles and thus sharing several biochemical pathways. Using a regulatory impact factor metric analysis, this regulatory network was further confirmed at the transcription factor and miRNA levels. In an extended cohort of 31 independent animals, multiple factor analysis confirmed the strong associations between lactate, methylene derivatives, miR-21-5p, miR-16-5p, let-7 family and genes that coded proteins involved in metabolic reactions primarily related to energy, ubiquitin proteasome and lipopolysaccharide immune responses after the endurance competition. Multiple factor analysis also identified potential biomarkers at T0 for an increased likelihood for failure to finish an endurance competition.
  
  
  
  To the best of our knowledge, the present study is the first to provide a comprehensive and integrated overview of the metabolome, transcriptome, and miRNome co-regulatory networks that may have a key role in regulating the metabolic and immune response to endurance exercise in horses.
authors.affiliation: Animal Genetics and Integrative Biology unit (GABI), INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France. nuria.mach@inra.fr.
authors.forename: Núria
authors.identifier: 0000-0002-8001-6314
authors.initials: N
authors.lastname: Mach
authors.affiliation: Animal Genetics and Integrative Biology unit (GABI), INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.
authors.forename: Yuliaxis
authors.initials: Y
authors.lastname: Ramayo-Caldas
authors.affiliation: Health Science Department, Open University of Catalonia (UOC), Barcelona, Spain.
authors.forename: Allison
authors.initials: A
authors.lastname: Clark
authors.affiliation: Animal Genetics and Integrative Biology unit (GABI), INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.
authors.forename: Marco
authors.initials: M
authors.lastname: Moroldo
authors.affiliation: Animal Genetics and Integrative Biology unit (GABI), INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.|Paris-Est University, National Veterinary School of Alfort, Maisons-Alfort, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Robert
authors.affiliation: Animal Genetics and Integrative Biology unit (GABI), INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Barrey
authors.affiliation: Health Science Department, Open University of Catalonia (UOC), Barcelona, Spain.
authors.forename: Jesús Maria
authors.initials: JM
authors.lastname: López
authors.affiliation: Integrative Biology of Exercise Adaptations unit, UBIAE, EA7362, Evry Val d'Essone University, Evry, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Le Moyec
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000818:Animals; D015415:Biomarkers / Q000097:blood; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006736:Horses; D055432:Metabolomics; D035683:MicroRNAs / Q000235:genetics*; D010805:Physical Conditioning, Animal / Q000502:physiology*; D010807:Physical Endurance / Q000235:genetics*; D049490:Systems Biology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D014157:Transcription Factors
keywords: Endurance exercise; Horse; Metabolome; Multiple factor analysis; Regulome; Systems biology; Transcriptome; miRNome