Human skeletal muscle disuse atrophy has profound and negative effects on the muscle metabolome and lipidome.

We investigated how short-term muscle disuse altered the skeletal muscle metabolome, lipidome, and transcriptome in middle-aged adults. We report that the energy metabolism pathways: nicotinate and nicotinamide metabolism, glycolysis, and TCA cycle, were reduced after 7 days of muscle disuse. These changes in the metabolome were reflected by changes in the transcriptome where multiple genes involved in glycolysis and TCA pathways were reduced after short-term disuse. Phenylalanine, tyrosine, and tryptophan metabolism pathways showed the same response and were reduced after short-term disuse. The skeletal muscle lipidome showed a decrease in phosphatidylinositols but an increase in phosphatidylglycerols and diacylglycerols after short-term muscle disuse. We conclude that short-term muscle disuse in humans has profound and negative effects on the muscle metabolome and lipidome. These include significant downregulation of muscle glycolytic, amino acid, and TCA cycle intermediates. In contrast, skeletal muscle lipids had a divergent response to disuse (e.g., increased phosphatidylglycerols and diacylglycerols, but reduced phosphatidylinositols).NEW & NOTEWORTHY We present the first study that has applied a multiomic analysis (metabolomics, lipidomics, and transcriptomics) of short-term disuse in middle-aged adults. We identified an altered lipidomic and metabolic signature after disuse that included increases in lipids associated with lipotoxicity (e.g., sphingomyelin and diacylglycerol) and reductions in phosphatidylinositol. Energy pathway metabolites for glycolysis and the TCA cycle were reduced after short-term disuse. The lipidomics and metabolomics data were supported by changes in the associated gene expression.