Oxytocin as a regulator of skeletal muscle plasticity and metabolic function

Although skeletal muscle has historically been considered a non-target tissue of oxytocin (OXT), accumulating evidence demonstrates that this neuropeptide influences myogenesis, regeneration, and protein metabolism, thereby modulating muscle plasticity through neuroendocrine signaling axes. Among physiological and pathological contexts, variations in circulating OXT are associated with changes in muscle mass. For example, anabolic steroid exposure promotes muscle hypertrophy alongside increased OXT levels, whereas aging and diabetes are characterized by muscle loss and reduced OXT. Mechanistically, OXT activates its receptor (OXTR), a G protein-coupled receptor, engaging Gαq signaling, intracellular calcium mobilization, and downstream pathways such as Akt-FoxO, thus linking central neuropeptide signaling to peripheral metabolic regulation. This crosstalk inhibits proteolysis while stimulating protein synthesis. Consistent with these findings, preclinical and clinical studies support a protective role of OXT in muscle mass regulation. However, key aspects of OXT biology in skeletal muscle remain poorly understood, including the regulation of its synthesis, degradation, and secretion under physiological and pathological conditions, which may influence its local and systemic actions. As a myokine, OXT may integrate local muscle signaling with systemic neuroendocrine actions, operating through autocrine, paracrine and endocrine mechanisms, although the relative contributions remain unresolved. In this context, emerging evidence on OXT signaling in skeletal muscle, particularly its role in regulating muscle plasticity, provides a conceptual framework that is explored throughout this review.