Multi-omics signatures of circulating factors associated with cardiorespiratory fitness adaptations in individuals with prediabetes

Abstract

Background: Patients with insulin resistance exhibit reduced cardiorespiratory fitness (CRF), assessed by peak oxygen consumption (VO₂peak), compared with healthy age-matched individuals. Although high- intensity interval training (HIIT) can substantially improve VO₂peak, there is considerable interindividual variability in this response. Therefore, further research is needed to elucidate the molecular mechanisms underlying the heterogeneous response of VO₂peak to HIIT in individuals with prediabetes. Methods: Proteomic analyses of serum samples, along with fecal metagenomic and targeted metabolomic profiling, were conducted in medication-naïve, overweight and obese Chinese men with prediabetes (n = 35; aged 24–62 years). All participants underwent a 12-week HIIT intervention, and biological samples were collected both before and after the intervention to evaluate exercise-induced alterations in circulating proteins, gut microbial composition, and metabolite profiles. Results: After 12 weeks of HIIT, mean VO₂peak increased by 0.47 L/min with individual responses ranging from 0 to 1.7 L/min. Baseline levels of short- chain fatty acid (SCFA)-producing genera, including Prevotella (β = 105.65, P = < 0.001, FDR = 0.034), Coprococcus (β = 50.22, P = 0.01, FDR = 0.39), and Hungatella (β = 40.72, P = 0.025, FDR = 0.50) , were positively associated with ΔVO₂peak. In contrast, baseline levels of the erythropoiesis- stimulating hormone erythropoietin (EPO) (β = −279.03, P = 0.024, FDR = 0.99) were negatively associated with ΔVO₂peak. Exercise-induced changes in growth hormone 1 (β = 63.97, P = 0.04, FDR = 0.99) were positively associated with ΔVO₂peak, whereas exercise-induced changes in BTB and CNC Homology 1 (β = −250.82, P = 0.01, FDR = 0.99), a repressor of heme oxygenase-1, were negatively associated with ΔVO₂peak. In multiple linear regression analysis including clinical variables, percentage lean mass (β = 64.17, P = 0.0005) was the strongest variable associated with ΔVO₂peak. The clinical model explained 27% of the variance which increased to 37% (P = 0.002) upon inclusion of exercise-associated circulating factors such as EPO. Conclusions: Our findings reveal that baseline proteomic and metagenomic signatures are associated with VO₂peak adaptations. These multi-omics signatures may support the clinical implementation of personalized exercise interventions to improve CRF in individuals with prediabetes.