Metabolic Predictors of Cardiorespiratory Fitness Responsiveness to Continuous Endurance and High-Intensity Interval Training Programs: The TIMES Study—A Randomized Controlled Trial

<b>Background/Objectives:</b> Cardiorespiratory fitness (CRF) levels significantly modulate the risk of cardiometabolic diseases, aging, and mortality. Nevertheless, there is a substantial interindividual variability in CRF responsiveness to a given standardized exercise dose despite the type of training. Predicting the responsiveness to regular exercise has the potential to contribute to personalized exercise medicine applications. This study aimed to identify predictive biomarkers for the classification of CRF responsiveness based on serum and intramuscular metabolic levels before continuous endurance training (ET) or high-intensity interval training (HIIT) programs using a randomized controlled trial. <b>Methods:</b> Forty-three serum and seventy intramuscular (vastus lateralis) metabolites were characterized and quantified via proton nuclear magnetic resonance (¹H NMR), and CRF levels (expressed in METs) were measured in 70 sedentary young men (age: 23.7 ± 3.0 years; BMI: 24.8 ± 2.5 kg·m^-2), at baseline and post 8 weeks of the ET, HIIT, and control (CO) periods. A multivariate binary logistic regression model was used to classify individuals at baseline as Responders or Non-responders to CRF gains after the training programs. <b>Results:</b> CRF responses ranged from 0.9 to 3.9 METs for ET, 1.1 to 4.7 METs for HIIT, and -0.9 to 0.2 METs for CO. The frequency of Responder/Non-responder individuals between ET (76.7%/23.3%) and HIIT (90.0%/10.0%) programs was similar (<i>p</i> = 0.166). The model based on serum O-acetylcarnitine levels [OR (odds ratio) = 4.72, <i>p</i> = 0.012] classified Responder/Non-responders individuals to changes in CRF regardless of the training program with 78.0% accuracy (<i>p</i> = 0.006), while the intramuscular model based on creatinine levels (OR = 4.53, <i>p</i> = 0.0137) presented 72.3% accuracy (<i>p</i> = 0.028). <b>Conclusions:</b> These results highlight the potential value of serum and intramuscular metabolites as biomarkers for the classification of CRF responsiveness previous to different aerobic training programs.