Excess muscle plasma membrane leak disrupts ECM content and shifts macrophage-mediated muscle repair
Abstract
Plasma membrane repair is critical for tissue integrity, especially for elongated contractile muscle cells. Genetically mediated defects in plasma membrane resealing produce persistent leak, leading to a disordered extracellular matrix (ECM). Loss of the membrane repair protein dysferlin slows sarcolemmal resealing and promotes excess leak. Annexin A6 is also implicated in sarcolemmal repair, forming repair caps at the site of membrane disruption. On its own, deletion of the gene for annexin A6, Anxa6, had little effect on muscle health. In contrast, combined loss of dysferlin and annexin A6 (DysfA6) generated muscle fibers with profoundly defective membrane leak. 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 ECM. In vitro, macrophages exposed to annexins A1 and A2 increased Csf1 expression, consistent with a model where excess leak results in annexins A1 and A2 in the ECM, where this protein composition influences macrophage proliferation and efferocytosis.
Authors
GaHyun Lee, Alexander J. Fitt, Ashlee M. Long, Lauren A. Vaught, Dorothy DeBiasse, Alexander R. Keeble, Jason M. Kwon, Patrick G.T. Page, Marie-Therese Daher, Michele Hadhazy, Alexander B. Willis, David Ceja Galindo, Maxwell McCabe, Connor Lantz, Kirk C. Hansen, Rachelle H. Crosbie, Edward B. Thorp, Alexis R. Demonbreun, Elizabeth M. McNally
Figure 6
Enhanced CASP3 expression and macrophage phagocytosis of myofibers with impaired membrane resealing.
