Excess muscle plasma membrane leak disrupts extracellular matrix content and shifts macrophage-mediated muscle repair [scRNA-Seq]

Strikingly, Anxa6 deletion in the context of loss of dystrophin (mdxA6) did not exacerbate muscle defects. The persistent membrane leak in DysfA6 muscle resulted in marked macrophage infiltration with disordered macrophage polarization. Injured muscle fibers were targets of macrophage efferocytosis.

Loss of Anxa6 was associated with increased expression of annexins A1 and A2, both of which were heavily deposited into the extracellular matrix. In vitro, macrophages exposed to annexins A1 and A2 expressed increased Csf1, consistent with a model where excess leak results in annexins A1 and A2 in the extracellular matrix, where this protein composition elicits macrophage proliferation and efferocytosis.