Metabolic exhaustion underlies sarcopenic obesity susceptibility in aging mice as revealed by multi-omics factor analysis

Background: Sarcopenic obesity (SO) affects up to 40% of older adults with obesity, yet many remain protected despite comparable metabolic burden. The molecular basis for this heterogeneity remains unknown. Methods: We exposed seventy-two 12-month-old female mice to high-fat diet (HFD) or standard diet for 7 months. Multi-Omics Factor Analysis integrated muscle transcriptomics and metabolomics to identify latent factors explaining phenotypic variation. Results: Despite uniform obesity development, aging HFD mice showed marked heterogeneity in muscle outcomes. Factor 3 uniquely distinguished dietary groups and predicted muscle dysfunction independent of adiposity severity. Factor 3 revealed metabolic exhaustion: despite coordinated upregulation of fatty acid oxidation genes (Fabp3, Lpl, Acadl) and oxidative markers, long-chain acylcarnitines accumulated and free L-carnitine depleted, indicating incomplete β-oxidation. Concurrent activation of p53, TNF/NFκB, and oxidative stress pathways indicated comprehensive metabolic decompensation. Plasma acetylcarnitine and pantothenol achieved AUC 0.91 for discriminating sarcopenia phenotypes. Conclusions: Individual susceptibility to sarcopenic obesity reflects differential metabolic exhaustion rather than obesity severity, detectable through circulating biomarkers.