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-α2. Secondary manifestations include failed regeneration, inflammation, and fibrosis; however, specific pathomechanisms remain unknown.

Objectives: Using the LAMA2^DyW (DyW) mouse model of MDC1A, we sought to determine if Integrin-αV 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 to WT levels with Losartan. Lastly, latent and active TGF-β 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.

Keywords: Congenital muscular dystrophy; ECM; Integrin; MDC1A; TGF-β.