Inhibition of Coxsackievirus-associated dystrophin cleavage prevents cardiomyopathy

J Clin Invest. 2013 Dec;123(12):5146-51. doi: 10.1172/JCI66271. Epub 2013 Nov 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Coxsackievirus Infections / metabolism
  • Coxsackievirus Infections / prevention & control*
  • Coxsackievirus Infections / virology
  • Cysteine Endopeptidases / physiology*
  • Cytopathogenic Effect, Viral
  • Dystrophin / chemistry
  • Dystrophin / genetics
  • Dystrophin / metabolism*
  • Enterovirus B, Human / enzymology*
  • Enterovirus B, Human / physiology
  • Gene Knock-In Techniques
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mutation
  • Myocarditis / metabolism
  • Myocarditis / prevention & control*
  • Myocarditis / virology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / virology
  • Proteolysis
  • Recombinant Fusion Proteins / metabolism
  • Sarcolemma / pathology
  • Transgenes
  • Viral Proteins / physiology*
  • Virus Replication


  • Dystrophin
  • Recombinant Fusion Proteins
  • Viral Proteins
  • apo-dystrophin 1
  • Cysteine Endopeptidases
  • picornain 2A, Picornavirus