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

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 LAMA2DyW (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.