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

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. We exposed 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 factors explaining phenotypic variation. 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. It revealed metabolic exhaustion: lipid overload-induced upregulation of fatty acid oxidation genes and oxidative markers, long-chain acylcarnitine accumulation, and free L-carnitine depletion, indicating incomplete β-oxidation. Activation of p53, TNF/NFκB, and oxidative stress pathways indicated comprehensive metabolic decompensation. Plasma acetylcarnitine and pantothenol achieved area under curve (AUC) 0.91 for discriminating sarcopenia phenotypes. Individual susceptibility to SO reflects differential metabolic exhaustion rather than obesity severity, detectable through circulating biomarkers.