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

Si-Jing Li, Xing-Ling He, Xiao-Jiao Zhang, Zi-Ru Li, Hui-Lin Liu, Yi-Hui Zhang, Min-Qi Lu, Jia-Hui Chen, Xiao-Ming Dong, Wen-Jie Long, Lu Lu, Zhong-Qi Yang, Shi-Hao Ni

State Key Laboratory of Traditional Chinese Medicine Syndrome, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Geriatrics Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Guangdong Clinical Research Institute of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.State Key Laboratory of Traditional Chinese Medicine Syndrome, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Geriatrics Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Guangdong Clinical Research Institute of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China. · pubmed

Paper

Abstract

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.

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Research summary

The paper claims that immunometabolic reprogramming of macrophages is crucial for skeletal muscle regeneration and can be targeted for therapeutic benefits. This research is relevant as it addresses the role of macrophages in muscle regeneration, which is a critical aspect of aging and age-related muscle degeneration, potentially offering insights into interventions that could mitigate age-related decline in muscle function.

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