Endogenous Amphiregulin promotes muscle repair and function through expansion of fibro-adipogenic progenitors during chronic Toxoplasma gondii infection in mice.

Skeletal muscle regeneration relies on coordinated interactions between immune cells and resident stem cell populations. While most studies have focused on sterile injury, the impact of infections on muscle repair remains less understood. Toxoplasma gondii, a widespread parasite that establishes chronic infection in skeletal muscle and also the central nervous system, induces myositis, fibrosis, and loss of muscle function. In mice, a natural intermediate host, chronic infection sustains a robust Th1 response dominated by IFNγ-producing CD4+ and CD8+ T cells. Regulatory T cells (Tregs), which normally promote resolution of inflammation, instead adopt a pathogenic phenotype, increasing inflammation and impairing repair. Amphiregulin (Areg), a ligand of the epidermal growth factor receptor, has been implicated in tissue repair by enhancing Treg function, promoting macrophage polarization, and supporting mesenchymal differentiation. While exogenous Areg improves muscle function during chronic T. gondii infection, the role of endogenous Areg remains unknown. Here, we used Areg-deficient mice to investigate its contribution to muscle repair during chronic infection. We show that Areg deficiency impaired Areg deficiency impaired fibro-adipogenic progenitor (FAP) expansion, reduced IFNγ-producing CD8+ T cells, and diminished the frequency of Tbet+ Tregs. Additionally, following CTX injury, Areg-deficient mice, particularly females, exhibited impaired regeneration characterized by smaller, more heterogeneous myofibers, and increased damaged area. These findings reveal a critical role for endogenous Areg in timely FAP expansion, proper effector and regulatory T cell polarization, and efficient muscle regeneration in the setting of chronic T. gondii infection.