Acute Exercise-Associated Metabolomic Remodeling and Associations with Oxidative State in Human Skeletal Muscle

Background: Acute exercise rapidly reorganizes skeletal-muscle metabolism. The metabolite pools that remain responsive with aging, and their relationship to baseline oxidative state, remain incompletely defined. Methods: We analyzed 135 metabolites measured in 93 skeletal-muscle biopsies from 47 participants and matched baseline transcriptomic measurements. We tested paired post-pre changes, biochemical-class enrichment, baseline associations with a four-pathway oxidative transcript-state score, and participant-held-out prediction of acetylcarnitine response. False-discovery-rate control was applied within each analysis family. Bootstrap confidence intervals and a baseline-adjusted sensitivity analysis quantified predictive performance. Results: In exercise-trained older adults, 17 metabolites changed after acute exercise after FDR correction. Acetylcarnitine increased, whereas free carnitine, malate, ATP, and choline decreased. No exercise-trained-versus-normally active response contrast survived correction. The CoA-glutathione-annotated feature and NAD⁺ remained associated with the oxidative transcript-state score after adjustment for group and sex (partial ρ=0.512 and 0.514; both q=0.042). A four-metabolite TabPFN model predicted acetylcarnitine change with an out-of-fold R2 of 0.412 (95% CI, 0.079-0.641), similar to the reference model (R2=0.399, 95% CI, 0.054-0.625). Baseline acetylcarnitine alone achieved an AUC of 0.817 (95% CI, 0.680-0.941) for a twofold-response endpoint. Additional metabolites provided only modest incremental information after baseline adjustment. Conclusions: Acute exercise induced heterogeneous, distributed remodeling of skeletal-muscle metabolite pools. Baseline redox-related molecular state showed cross-omic coherence and contained information about subsequent acetylcarnitine response. Transcriptomic augmentation and more complex predictive architectures provided limited incremental benefit.