Metrnl and macrophage polarization: role in skeletal muscle homeostasis and therapeutic potential

Macrophage polarization has a significant influence on the immune microenvironment of skeletal muscle, regulating metabolic and repair homeostasis. Meteorin-like protein (Metrnl), a recently identified myokine, is implicated in immunity, metabolism, and tissue remodeling. It regulates macrophage polarization through a complex, integrated signaling network, conferring multiple metabolic benefits on skeletal muscle. This review outlines the dynamics of macrophage polarization in maintaining skeletal muscle homeostasis and discusses the signaling pathways through which Metrnl exerts its effects. Drawing on human and rodent in vivo studies, the focus is on the pivotal role of this regulatory axis in skeletal muscle destabilization, particularly in glucose metabolic disorders and age-related sarcopenia. Notably, Metrnl acts as a bidirectional regulator whose biological effects are highly tissue- and disease-dependent. The review further concludes by examining potential pathological mechanisms linking Metrnl-modulated macrophage polarization to skeletal muscle microenvironmental homeostasis, and highlights unresolved questions regarding Metrnl receptor distribution and subset-specific macrophage regulation, putting forward multi-omics and in vivo imaging technologies as core avenues for subsequent exploration.