Inhibition of Coxsackievirus-associated dystrophin cleavage prevents cardiomyopathy
Byung-Kwan Lim, … , Ju Chen, Kirk U. Knowlton
Byung-Kwan Lim, … , Ju Chen, Kirk U. Knowlton
Published November 8, 2013
Citation Information: J Clin Invest. 2013;123(12):5146-5151. https://doi.org/10.1172/JCI66271.
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Inhibition of Coxsackievirus-associated dystrophin cleavage prevents cardiomyopathy

Abstract

Heart failure in children and adults is often the consequence of myocarditis associated with Coxsackievirus (CV) infection. Upon CV infection, enteroviral protease 2A cleaves a small number of host proteins including dystrophin, which links actin filaments to the plasma membrane of muscle fiber cells (sarcolemma). It is unknown whether protease 2A–mediated cleavage of dystrophin and subsequent disruption of the sarcolemma play a role in CV-mediated myocarditis. We generated knockin mice harboring a mutation at the protease 2A cleavage site of the dystrophin gene, which prevents dystrophin cleavage following CV infection. Compared with wild-type mice, we found that mice expressing cleavage-resistant dystrophin had a decrease in sarcolemmal disruption and cardiac virus titer following CV infection. In addition, cleavage-resistant dystrophin inhibited the cardiomyopathy induced by cardiomyocyte-restricted expression of the CV protease 2A transgene. These findings indicate that protease 2A–mediated cleavage of dystrophin is critical for viral propagation, enteroviral-mediated cytopathic effects, and the development of cardiomyopathy.

Authors

Byung-Kwan Lim, Angela K. Peter, Dingding Xiong, Anna Narezkina, Aaron Yung, Nancy D. Dalton, Kyung-Kuk Hwang, Toshitaka Yajima, Ju Chen, Kirk U. Knowlton

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Figure 3

Prevention of dystrophin cleavage in DysKI/2A/MCM mice inhibits enteroviral protease 2A–mediated cardiomyopathy.

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Prevention of dystrophin cleavage in DysKI/2A/MCM mice inhibits enterovi...
(A) Whole hearts from control mice (see text), mice harboring wild-type dystrophin, protease 2A, and the MerCREMer transgenes (DysWT/2A/MCM), and mice harboring the dystrophin knockin, protease 2A, and the MerCREMer transgenes (DysKI/2A/MCM). Hearts were taken from these mice 4 weeks after tamoxifen administration and demonstrate that dystrophin knockin inhibited the gross appearance of dilated cardiomyopathy. (B) Echocardiographic parameters 4 weeks after tamoxifen administration. Left ventricular end-systolic dimension (LVESd), left ventricular end-diastolic dimension (LVEDd), and fractional shortening were significantly better in DysKI/2A/MCM mice than in DysWT/2A/MCM mice 4 weeks after the induction of protease 2A expression. Data represent the mean ± SEM. *P < 0.05, **P < 0.01; each data point is represented on the graphs. (C) The percentage of overall area showing EBD uptake (white stain, see arrow) was significantly reduced in DysKI/2A/MCM mice compared with DysWT/2A/MCM mice. Data represent the mean ± SEM. *P ≤ 0.05. Scale bar: 500 μm. (D) H&E, trichrome, and picrosirius red staining demonstrate that there was less fibrosis in DysKI/2A/MCM mice compared with DysWT/2A/MCM mice. Fibrosis was quantified using picrosirius red staining in 4 DysWT/2A/MCM and 4 DysKI/2A/MCM mice. Data represent the mean ± SEM. *P ≤ 0.05; **P < 0.01. Scale bar: 200 μm. (E) eIF4GI cleavage was detected in both DysWT/2A/MCM and DysKI/2A/MCM mouse hearts (arrow), but not in control hearts without protease 2A expression. Dystrophin cleavage was not detectable by Western blotting (not shown).