Bortezomib Does Not Reduce Muscular Dystrophy in the dy.sup.2J/dy.sup.2J Mouse Model of Laminin [alpha]2 Chain-Deficient Muscular Dystrophy

Congenital muscular dystrophy with laminin [alpha]2 chain-deficiency, also known as MDC1A, is a severe neuromuscular disorder for which there is no cure. Patients with complete laminin [alpha]2 chain-deficiency typically have an early onset disease with a more severe muscle phenotype while patients with residual laminin [alpha]2 chain expression usually have a milder disease course. Similar genotype-phenotype correlations can be seen in the dy.sup.3K /dy.sup.3K and dy.sup.2J /dy.sup.2J mouse models of MDC1A, respectively, with dy.sup.3K /dy.sup.3K mice presenting the more severe phenotype. Recently, we demonstrated that the proteasome inhibitor bortezomib partially improves muscle morphology and increases lifespan in dy.sup.3K /dy.sup.3K mice. Here, we explore the use of bortezomib in dy.sup.2J /dy.sup.2J animals. However, bortezomib neither improved histological hallmarks of disease nor increased muscle strength and locomotive activity in dy.sup.2J /dy.sup.2J mice. Altogether our data suggest that proteasome inhibition does not mitigate muscle dysfunction caused by partial laminin [alpha]2 chain-deficiency. Still, it is possible that proteasome inhibition could be useful as a supportive therapy in patients with complete absence of laminin [alpha]2 chain.