Key result
MG132 restores Nav1.5 expression and cardiac sodium current to control levels in dystrophin-deficient mice.
Why the study?
Nav1.5 protein content and sodium current are decreased in cardiomyocytes of dystrophin-deficient mdx (5cv) mice, and the mechanism of this reduction was unclear.
Does proteasome inhibitor MG132 improve Nav1.5 protein content and sodium current in dystrophin-deficient mdx(5cv) mice?
Does proteasome inhibitor MG132 improve Nav1.5 protein content and sodium current in dystrophin-deficient mdx(5cv) mice?
Proteasome inhibition rescues cardiac sodium channel Nav1.5 expression and function in dystrophin-deficient mice, indicating its reduction is driven by proteasomal degradation.
Hypothesis-generating for proteasome inhibition to restore Nav1.5 in dystrophin deficiency; leaves open translation to human DMD cardiomyopathy.
The cardiac voltage-gated sodium channel, Nav1.5, plays a central role in cardiac excitability and impulse propagation and associates with the dystrophin multiprotein complex at the lateral membrane of cardiomyocytes. It was previously shown that Nav1.5 protein content and the sodium current (l Na) were both decreased in cardiomyocytes of dystrophin-deficient mdx (5cv) mice. In this study, wild-type and mdx (5cv) mice were treated for 7 days with the proteasome inhibitor MG132 (10 μg/Kg/24 h) using implanted osmotic mini pumps. MG132 rescued both the total amount of Nav1.5 protein and l Na but, unlike in previous studies, de novo expression of dystrophin was not observed in skeletal or cardiac muscle. This study suggests that the reduced expression of Nav1.5 in dystrophin-deficient cells is dependent on proteasomal degradation.
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Rougier et al. (2013) studied Dystrophin-deficiency. MG132 vs. 0.9% NaCl was evaluated on Nav1.5 protein content and cardiac sodium current (INa). MG132 treatment rescued Nav1.5 expression and the cardiac sodium current in cardiomyocytes of dystrophin-deficient mdx5cv mice to levels similar to control mice, without restoring dystrophin expression.
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