Integrin dysregulation as a possible driver of matrix remodeling in Laminin-deficient congenital muscular dystrophy (MDC1A)

Abstract

Background: Merosin-deficient congenital muscular dystrophy (MDC1A) is caused by a loss of Laminin-2. Secondary manifestations include failed regeneration, inflammation, and fibrosis; however, specific pathomechanisms remain unknown. Objectives: Using the LAMA2DyW (DyW) mouse model of MDC1A, we sought to determine if Integrin-α V and-α5, known drivers of pathology in other diseases, are dysregulated in dystrophic muscle. Additionally, we investigated whether Losartan, a drug previously shown to be antifibrotic in dystrophic scenarios, rescues integrin overexpression in DyW mice. Methods: qRT-PCR, ELISA, and immunohistochemistry were utilized to characterize integrin and matricellular protein dysregulation in hind limb muscles from WT and untreated/ Losartan-treated DyW mice. Results: Integrin-αV and-α5 are significantly upregulated on both gene and protein level in DyW muscle-Losartan treatment attenuates this dysregulation. Immunohistochemistry showed that Integrin-αV is expressed on both infiltrating cells as well as on muscle cells-Losartan attenuates expression in both compartments. In addition, transcriptional overexpression of common matricellular and beta binding partners is rescued close toWTlevels with Losartan. Lastly, latent and active TGFβ are upregulated in the serum of DyW mice, but only active TGF-β levels are attenuated by Losartan treatment. Conclusions: Our results suggest that overexpression of Integrin-αV and-α5 are likely contributing to secondary pathologies in MDC1A. We also believe that downregulation of Integrin-αV could be partially responsible for Losartan's antifibrotic effect and therefore could serve as a novel therapeutic target in MDC1A and other degenerative fibrotic diseases.