Dysferlin promotes inflammatory macrophage responses and modulates Ca2+-dependent STAT1 signaling.

Macrophage differentiation and activation shape tissue homeostasis and regeneration. Dysferlin (DYSF) is best known for its role in membrane repair in skeletal muscle, but its function in immune cells remains poorly understood. Here, we identify DYSF as a regulator of inflammatory macrophage-associated activation. DYSF expression increased during monocyte-to-macrophage differentiation. Gain- and loss-of-function analyses revealed that DYSF promoted inflammatory macrophage-associated responses, including cytokine production and migration. DYSF also enhanced Ca2+ influx and STAT1 Ser727-associated signaling, whereas Dysf knockdown or Ca2+ entry inhibition suppressed these responses. DYSF expression increased with aging in human CD14-positive cells and mouse monocyte/macrophage-lineage cells, and DYSF-expressing F4/80-positive macrophage-lineage cells accumulated in aged skeletal muscle. In a macrophage-myoblast co-culture system, DYSF-enriched inflammatory macrophages inhibited myogenic differentiation and myotube fusion, with this effect being partially mediated by soluble inflammatory factors, demonstrating an influence of macrophage DYSF on neighboring myogenic cells in vitro. Together, these findings support a role for DYSF in Ca2+-dependent STAT1-associated inflammatory responses in macrophages and in the suppression of myogenesis in cellular models.