M.I.3 The role of laminins in myomatrix assembly and skeletal muscle stability

Abstract

The basement membrane of skeletal muscle (myomatrix) consists of a complex network of highly glycosylated proteins. Important components of the myomatrix are the laminins and the collagens. During development, the myomatrix is assembled by interactions with cell surface receptors and by self-polymerization, which results in an extracellular scaffold important for skeletal muscle stability. Mutations in the α2 chain of laminin-211 impinge on myomatrix assembly and its interaction with cell surface receptors, and result in one of the most severe forms of congenital muscular dystrophy (MDC1A). Based on a detailed mechanistic understanding of the function of laminin-211, we have designed artificial linker molecules derived from agrin or perlecan with the aim to bridge the remaining myomatrix to cell surface receptors. In the conducted preclinical, proof-of-concept studies we were able to show that they can substantially ameliorate the disease phenotype in a mouse model of MDC1A. Subsequent approaches to further improve the treatment have focused on testing interventions that affect downstream pathways, such as apoptosis and inflammation, using pharmacological and genetic tools. All those treatments show additional beneficial effects on disease progression. However, semi-quantitative comparison of the treatments indicates that interventions that target early events in the disease are more efficacious than those targeting further downstream pathways. Finally, we will also report on the ongoing efforts to combine interventions that boost myomatrix assembly with those that connect it to skeletal muscle receptors. In summary, we will report on proof-of-concept studies that provide mechanistic insights and unequivocal preclinical evidence for the potential use of those therapies. As the MDC1A mice used in our studies share many hallmarks with the human disease, these preclinical data may be of high predictive value for future clinical studies.