Multidimensional biocircuitry of exercise adaptation: integratingin vivoandex vivophenomics with miRNA mapping

ABSTRACT In a randomized, dose-response trial, we used molecular and phenomic profiling to compare responses to traditional (TRAD) moderate intensity endurance and resistance training vs. high-intensity tactical training (HITT) that encompassed explosive whole-body interval training and high-intensity resistance training. Ninety-four participants (18-27 years) completed 12 weeks of TRAD or HITT followed by 4 weeks of detraining. Although similar performance and body composition improvements were observed in response to HITT and TRAD, some dose-dependent differences were observed for: (i) ex vivo muscle tissue changes in myofiber size, capillarization, satellite cell frequency, and mitochondrial function; and (ii) differential gene expression (DGE) of muscle and serum exosomal miRNAs (miRs). However, these dose-dependent ex vivo muscle adaptations were overshadowed by wide-ranging inter-individual response heterogeneity (IRH). We therefore explored IRH by first establishing minimum clinically important difference (MCID) scores to classify each participant based on MCIDs for functional muscle quality (fMQ) and cardiorespiratory fitness (CRF), and then modeling all data based on MCID classification. Using higher-order singular value decomposition (HOSVD), we established multidimensional biocircuitry linked to IRH that identified the most influential features across lifestyle, body composition, performance, ex vivo muscle tissue, and miRNA mapping domains. Via cross-comparison of MCID-linked miRs identified via DGE and HOSVD, nine miRs emerged as robust features of training adaptability, providing new insights into the integrated biocircuitry driving IRH. NEW & NOTEWORTHY We examined in vivo and ex vivo adaptations to TRAD (traditional moderate-intensity endurance and resistance training) vs. HITT (high-intensity tactical training; explosive whole-body interval training and high-intensity resistance training). TRAD and HITT improved physiological performance and body composition, and induced ex vivo muscle adaptations, with remarkable inter-individual response heterogeneity (IRH) in improvements. We leveraged multidimensional modeling to identify IRH biocircuitry that integrates deep phenotyping and miR transcriptomics (serum exosomes, skeletal muscle). Competing Interest Statement The authors have declared no competing interest. Clinical Trial NCT03380923 Funding Statement This study was funded by a US Department of Defense Multidisciplinary University Research Initiative (MURI) awarded and administered via the Office of Naval Research under grant N000141613159. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board for Human Use of the University of Alabama at Birmingham gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Data Availability All data produced in the present study are available upon reasonable request to the authors.