Dual role of macrophages in skeletal muscle atrophy: Mechanisms and therapeutic strategies.

Abstract

Skeletal muscle atrophy represents a pathological condition characterized by impaired protein homeostasis that commonly occurs with aging, chronic inflammatory diseases, physical inactivity, and neuromuscular disorders. This condition significantly reduces patients' quality of life and increases mortality risk. Emerging research highlights the immune system, especially macrophages, as key regulators of this process. As core components of innate immunity, macrophages exhibit high plasticity and orchestrate muscle repair and the regulation of chronic inflammation through polarized pro-inflammatory (M1) and anti-inflammatory/reparative (M2) phenotypes. This review systematically examines the dual role of macrophages in muscle pathology. On one hand, they facilitate muscle regeneration by removing necrotic tissue and secreting growth factors like Insulin-like Growth Factor 1 (IGF-1) and Interleukin-10 (IL-10) to promote satellite cell activation. On the other hand, improper macrophage activation or polarization shifts toward sustained M1 dominance can release harmful cytokines such as Tumor Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6), activating Nuclear Factor-kappa B (NF-κB) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways that increase protein breakdown, inhibit muscle formation, and accelerate atrophy. Additionally, we evaluate macrophage-focused treatments including drug inhibitors, stem cell therapies, plant compounds that modify polarization, and genetic approaches to rebalance immune function and reduce muscle wasting. Collectively, these advances provide novel mechanistic insights into immune-mediated skeletal muscle pathology and lay the groundwork for a translational framework for targeted interventions.