Immunometabolic reprogramming of macrophages: Emerging roles in skeletal muscle regeneration and therapeutic perspectives.

Skeletal muscle regeneration is a complex and strictly regulated process that involves complex interactions between immune cells, muscle-resident progenitor cells, and stromal components. Macrophages play a central role in this process by coordinating immune responses, supporting regeneration, and promoting tissue remodeling through phenotypic transitions that respond to environmental cues. Under physiological conditions, these transitions ensure efficient tissue restoration. However, in pathological settings or conditions such as aging, muscular dystrophy, cancer cachexia, and metabolic disorders, macrophage function becomes dysregulated. This situation often leads to persistent inflammation, excessive fibrosis, and impaired regeneration of muscle tissue. Recent advances in single-cell and spatial transcriptomics technologies have revealed the remarkable heterogeneity of macrophage subpopulations within skeletal muscle. These findings emphasize the importance of immunometabolic programming as a key driver of macrophage plasticity. Shifts in glucose metabolism, oxidative phosphorylation, lipid utilization, and amino acid pathways critically influence the polarization of macrophages and their interactions with surrounding cells. Moreover, metabolic signals from the tissue microenvironment, circulating factors, and muscle-resident cells create a dynamic network of metabolic crosstalk that shapes macrophage behavior. This review provides a comprehensive summary of how macrophage immunometabolism regulates skeletal muscle regeneration in both acute injury and chronic disease. It highlights core metabolic pathways, macrophage-centered intercellular communication, and emerging therapeutic strategies that aim to reprogram macrophage metabolism for a regenerative benefit. In addition, key challenges and future directions for translating these insights into effective interventions for muscle wasting conditions are discussed.