In a randomized, dose-response trial, we used molecular and phenomic profiling to compare responses to traditional (TRAD) endurance plus resistance training and high-intensity tactical training (HITT). Ninety-four participants (18-27 years) completed 12 weeks of TRAD or HITT followed by 4 weeks of detraining. While in vivo phenotype improvements were not dose-dependent, a few dose-dependent ex vivo muscle adaptations were overshadowed by wide-ranging inter-individual response heterogeneity (IRH). To address this, we established minimum clinically important difference (MCID) scores to classify participants by their attainment of MCIDs for functional muscle quality (fMQ) and cardiorespiratory fitness (CRF). Using differential gene expression (DGE) of muscle and exosomal microRNAs (miRs) and higher-order singular value decomposition (HOSVD), we mapped the molecular and phenomic biocircuitry of IRH. Nine miRs emerged as robust features of training adaptability, providing new insights into the integrated biocircuitry driving exercise adaptations and response heterogeneity.

In brief We examined in vivo and ex vivo adaptations to two randomized exercise prescriptions. Individual response variability overshadowed dose dependent effects. Deep phenotyping and miR transcriptomics of serum exosomes and skeletal muscle enabled multidimensional modeling of integrated biocircuits linked to attaining clinically significant outcomes.

The authors have declared no competing interest.

NCT03380923

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.

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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.

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All data produced in the present study are available upon reasonable request to the authors.