This systematic review aimed to synthesize evidence on skeletal muscle metabolic determinants of inter-individual variation in weight and fat loss responses to exercise-based and combined lifestyle interventions. Responses to exercise and lifestyle interventions exhibit substantial inter-individual variability, particularly in weight and fat loss. Despite similar exercise prescriptions, many individuals show minimal or no improvements in body composition. Accumulating evidence indicates that skeletal muscle metabolic characteristics may underlie this variability. A systematic search was conducted in PubMed/MEDLINE, Scopus, and Web of Science following PRISMA guidelines. Eligible studies included adult human interventions reporting responder and non-responder phenotypes for weight or fat loss outcomes and incorporating skeletal muscle metabolic, molecular, or phenotypic assessments. Findings were qualitatively synthesized with emphasis on mitochondrial function, metabolic pathways, metabolomic profiles, and molecular or genetic markers related to skeletal muscle metabolism. Included studies consistently demonstrated marked heterogeneity in weight and fat loss responses despite comparable intervention protocols. Non-response emerged as a reproducible and biologically meaningful phenomenon rather than random variation. Differential responsiveness was associated with skeletal muscle metabolic features, such as mitochondrial oxidative capacity, amino acid metabolism, metabolomic signatures, adipokine profiles, and genetic variation, related to mitochondrial function. Importantly, group-level mean effects often masked clinically relevant responder and non-responder subgroups. Skeletal muscle metabolic phenotype appears to be a key determinant of inter-individual variation in weight and fat loss responses to exercise and lifestyle interventions. These findings support phenotyping-based, precision-oriented exercise strategies that account for biological heterogeneity.
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