Improving Reproducibility of Phenotypic Assessments in the DyW Mouse Model of Laminin-α2 Related Congenital Muscular Dystrophy

Abstract

Laminin-α2 related Congenital Muscular Dystrophy (LAMA2-CMD) is a progressive muscle disease caused by partial or complete deficiency of laminin-211, a skeletal muscle extracellular matrix protein. In the last decade, basic science research has queried underlying disease mechanisms in existing LAMA2-CMD murine models and identified possible clinical targets and pharmacological interventions. Experimental rigor in preclinical studies is critical to efficiently and accurately quantify both negative and positive results, degree of efficiency of potential therapeutics and determine whether to move a compound forward for additional preclinical testing. In this review, we compare published available data measured to assess three common parameters in the widely used mouse model DyW, that mimics LAMA2-CMD, we quantify variability and analyse its possible sources. Finally, on the basis of this analysis, we suggest standard set of assessments and the use of available standardized protocols, to reduce variability of outcomes in the future and to improve the value of preclinical research.

A Family of Laminin α2 Chain-Deficient Mouse Mutants: Advancing the Research on LAMA2-CMD

“…The respiratory function in dy W /dy W mice has also been evaluated by whole-body plethysmography. However, the breath rate did not appear to change over time and may not be predictive of pathology in dy W /dy W animals (Willmann et al, 2017). Analysis of cardiac muscle in this mouse model is required.…”

“…Variability in growth rates and overall survival of dy W /dy W animals from different laboratories have been noted (Willmann et al, 2017) and such discrepancies are likely to occur for the other mouse models as well. Therefore, it may be highly relevant to replicate the different therapeutic strategies in different mouse models and in different laboratories (even though such studies will be difficult to publish).…”

“…Basement membranes have patchy appearance in dy W /dy W muscle (Moll et al, 2001). The dystrophic changes described above correlate with impaired muscle function (Moll et al, 2001;Doe et al, 2011;Willmann et al, 2017).…”

“…Only recently the importance of the embryonic, pre-symptomatic stages and early pathogenesis in the different mouse models for LAMA2-CMD has been emphasized Mehuron et al, 2014;Nunes et al, 2017;Moreira Soares Oliveira et al, 2018). Likewise, associated symptoms in non-muscle tissues (peripheral and central nervous system, cardiorespiratory system) have gained attention (Hager et al, 2005;Qiao et al, 2005Qiao et al, , 2018Yang et al, 2005;Gawlik et al, 2006a, 2018, Homma et al, 2011Menezes et al, 2014;Willmann et al, 2017;Pasteuning-Vuhman et al, 2018;Rabie et al, 2019).…”

Zebrafish Models of LAMA2-Related Congenital Muscular Dystrophy (MDC1A)

“…Studies of animal models of muscular dystrophies have proven essential for a better understanding of the pathogenesis of these disorders and for developing disease-specific therapies (Saunier et al, 2016 ; Widrick et al, 2019 ). Research using mouse models for LAMA2-MD have identified potential therapeutic strategies, which, in turn, have led to improvements in murine disease pathology and survival (Miyagoe-Suzuki et al, 2000 ; Meinen et al, 2007 , 2011 ; Vishnudas and Miller, 2009 ; McKee et al, 2017 ; Reinhard et al, 2017 ; Willmann et al, 2017 ; Mohassel et al, 2018 ; Yurchenco et al, 2018 ).…”