Bortezomib Does Not Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy

Abstract

Congenital muscular dystrophy with laminin α2 chain-deficiency, also known as MDC1A, is a severe neuromuscular disorder for which there is no cure. Patients with complete laminin α2 chain-deficiency typically have an early onset disease with a more severe muscle phenotype while patients with residual laminin α2 chain expression usually have a milder disease course. Similar genotype-phenotype correlations can be seen in the dy3K/dy3K and dy2J/dy2J mouse models of MDC1A, respectively, with dy3K/dy3K mice presenting the more severe phenotype. Recently, we demonstrated that the proteasome inhibitor bortezomib partially improves muscle morphology and increases lifespan in dy3K/dy3K mice. Here, we explore the use of bortezomib in dy2J/dy2J animals. However, bortezomib neither improved histological hallmarks of disease nor increased muscle strength and locomotive activity in dy2J/dy2J mice. Altogether our data suggest that proteasome inhibition does not mitigate muscle dysfunction caused by partial laminin α2 chain-deficiency. Still, it is possible that proteasome inhibition could be useful as a supportive therapy in patients with complete absence of laminin α2 chain.

Antioxidants Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy

“…As previously described, we observed a decrease in dy 2J /dy 2J forelimb grip strength at six weeks of age [25,32] (Figure 2A,C). Notably, NAC treatment significantly prevented grip strength reduction in dy 2J /dy 2J mice (Figure 2A).…”

“…One of the typical characteristics of laminin α2 chain-deficiency is pathological fibrosis, which has been shown to be increased 2.5-fold in dy 2J /dy 2J quadriceps and triceps muscles compared with wild-type muscles [32]. We measured fibrosis by both morphometric and colorimetric evaluation of Fast Green and Sirius Red-stained sections.…”

Antioxidants Reduce Muscular Dystrophy in the dy^2J/dy^2J Mouse Model of Laminin α2 Chain-deficient Muscular Dystrophy

“…As previously described, we observed a decrease in dy 2J /dy 2J forelimb grip strength at six weeks of age [25,27] ( Figure. 2A, 2C).…”

“…One of the typical characteristics of laminin α2 chain-deficiency is pathological fibrosis, which has been shown to be increased 2.5-fold in dy 2J /dy 2J quadriceps and triceps muscles compared with wild-type muscles [27]. We measured fibrosis by both morphometric and colorimetric evaluation of Fast Green and Sirius Red-stained sections.…”

<p>Current understanding and treatment of cardiac and skeletal muscle pathology in laminin-α2 chain-deficient congenital muscular dystrophy</p>

“…Systemic treatment with bortezomib, a more selective proteasome inhibitor, likewise resulted in significant improvements in the same model 128. However, proteasome inhibition in general only achieves partial recovery at best and is not particularly useful for treating partial laminin-α2 deficiency 129. The same can be said for the therapeutic efficacy of 3-methyladenine, an inhibitor of autophagy 130.…”