Plasma high‐resolution metabolomic phenotyping of lean mass in a United States adult cohort

Background Rapid loss of lean mass during catabolic states is associated with impaired convalescence and increased mortality rates. An understanding of metabolic pathways related to lean mass is needed to enable future interventions designed to combat malnutrition. This study assessed the plasma metabolome in relation to lean mass in clinically stable working adults in a US cohort. Methods This cross‐sectional study included 180 adults (mean ± SD, aged 49.7 ± 10.0 years; body mass index, 27.3 ± 5.5 kg/m2; 64% female [n=116]). Fasting plasma was analyzed using high‐resolution metabolomics (HRM) via liquid chromatography/mass spectrometry. Lean mass was assessed by dual‐energy x‐ray absorptiometry and expressed as lean mass index (LMI, lean mass kg/height m2). Multiple linear regression, metabolic pathway enrichment, and module analyses were used to characterize systemic metabolism associated with LMI. Results Of 5360 metabolites used in analyses, 593 were related to LMI, either upregulated or downregulated (P < .05). These were enriched within 11 metabolic pathways, including branched‐chain amino acid degradation, metabolism of alanine and aspartate and other amino acids, butyrate, purines, and niacin metabolism. Module analysis revealed central associations between LMI and L‐glutamate, L‐leucine/L‐isoleucine, L‐valine, L‐phenylalanine, L‐methionine, and L‐aspartate, among other validated metabolites. Conclusion These novel plasma HRM data demonstrate the wide‐reaching associations of lean mass with systemic metabolism in a single snapshot. Such data may inform targeted nutrition support interventions designed to mitigate loss of lean mass and promote regaining skeletal muscle mass and function after illness or injury.