Multi-dimensional metabolomic remodeling under diverse muscle atrophic stimuli in vivo

Muscle wasting leads to reduced activities of daily living, an increased number of care-dependent individuals, and increased mortality. However, the metabolomic adaptations underlying muscle wasting remain poorly understood. Here, by comparing physiological, genetically induced, pathological, and age-related muscle atrophy, we identify the metabolites modulated by muscle atrophic stimuli, which we term "atrometabolites." Integrated metabolomics reveal that dysfunctional polyamine synthesis is a common feature of muscle atrophy. Mechanistically, we identify that adenosylmethionine decarboxylase 1 (Amd1) and Amd2 are important for maintaining polyamine metabolism and that downregulation of Amd1 and Amd2 is a trigger of myotube atrophy. Using skeletal muscle-specific FoxO triple-knockout mice, we find that FoxOs are required for immobilization-induced metabolomic remodeling and identify FoxO-dependent atrometabolites. This study comprehensively elucidates the molecular basis of muscle metabolomic adaptation and provides the datasets that will lead to the discovery of mechanisms underlying tissue adaptation to maintain homeostasis.