Macrophages in the pathogenesis of monogenic muscular dystrophies: inflammation, fibrosis, and therapeutic implications

Monogenic muscular dystrophies (MDs), such as Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy (LGMD), are characterized by chronic inflammation, progressive fibrosis, and impaired muscle regeneration. Central to these pathological processes are macrophages, which exhibit dynamic polarization states that influence the dystrophic microenvironment. In early disease stages, macrophages support tissue repair and regeneration, but chronic inflammation skews their activity toward pro-fibrotic phenotypes, driving excessive extracellular matrix (ECM) deposition and muscle dysfunction. Macrophages also interact with other immune cells, such as T cells and neutrophils, and non-immune cells, including fibroblasts and satellite cells, to regulate inflammatory and fibrotic responses. These interactions establish a dysregulated immune environment that exacerbates muscle damage and impairs effective regeneration. Preclinical studies using the mdx mouse model of DMD highlight the critical role of macrophages in sustaining inflammation and fibrosis, particularly through transforming growth factor-beta (TGF-β) signaling and fibro-adipogenic progenitor (FAP) activation. Therapeutically, targeting macrophages offers significant potential to mitigate disease progression. Strategies include modulating macrophage polarization toward a pro-regenerative M2 phenotype, inhibiting macrophage recruitment via chemokine signaling, and reprogramming macrophage metabolism to support oxidative phosphorylation and mitochondrial function. Additionally, anti-fibrotic interventions targeting TGF-β signaling or macrophage-FAP crosstalk have shown promise in reducing ECM deposition and preserving muscle architecture. In this review, we curate relevant studies and provide insights into the molecular mechanisms governing macrophage behavior in dystrophic muscle. Herein, we discuss how emerging therapeutic strategies targeting macrophage-mediated pathways can be leveraged to mitigate inflammation and fibrosis, enhance muscle regeneration, and improve clinical outcomes.