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Summary: Skeletal muscle generation of ammonia, an endogenous cytotoxin, is increased during exercise. Perturbations in ammonia metabolism consistently occur in chronic diseases, and may blunt beneficial skeletal muscle molecular responses and protein homeostasis with exercise. Phosphorylation of skeletal muscle proteins mediates cellular signaling responses to hyperammonemia and exercise. Comparative bioinformatics and machine learning-based analyses of published and experimentally derived phosphoproteomics data identified differentially expressed phosphoproteins that were unique and shared between hyperammonemic murine myotubes and skeletal muscle from exercise models. Enriched processes identified in both hyperammonemic myotubes and muscle from exercise models with selected experimental validation included protein kinase A (PKA), calcium signaling, mitogen-activated protein kinase (MAPK) signaling, and protein homeostasis. Our approach of feature extraction from comparative untargeted “omics” data allows for selection of preclinical models that recapitulate specific human exercise responses and potentially optimize functional capacity and skeletal muscle protein homeostasis with exercise in chronic diseases.