Researchers at the University of Minnesota have gained new insights into the relationship between enterovirus infection, heart function, and the protein dystrophin, better known for its role in Duchenne's muscular dystrophy.

They published their results in the July 1, 2015, issue of Science Translational Medicine.

"Our paper looks at the structure-function relationship of dystrophin, [and] dystrophin's role in the heart," lead author Matthew Barnabei told BioWorld Today.

It also broadens the scope of dystrophin's role in disease.

"I don't think people pay as much attention to it in the context of a non-inherited disease," Barnabei said. But "there is significant evidence that dystrophin is disrupted in numerous types of non-inherited disease states," including cardiomyopathy.

Dystrophin plays an important role in Duchenne muscular dystrophy, an X-linked recessive disorder. It plays an important structural role, and mutations leaving it nonfunctional lead to the progressive skeletal muscle weakness that is the disease's signature feature, but also an increased risk of neurobehavioral problems. In later stages, the disease also affects the heart and breathing muscles.

Enteroviruses, as a group, most often lead to gastrointestinal problems. But some members of the family, including Coxsackievirus, can infect the heart – and can lead to serious heart problems when they do so, including sudden death due to a heart attack.

How frequently this worst-case scenario occurs is not clear, but one study found tell-tale signs of enterovirus infection in 20 percent to 40 percent of people who had a sudden fatal heart attack.

Previous work had shown that one of the consequences of cardiac Coxsackievirus infection is that a viral protease cuts dystrophin, which suggested that dysfunctional dystrophin might be one of the reasons that the infection can spell such serious trouble for the heart.

But it was unclear whether the problem was that there was no dystrophin, or whether the dystrophin fragments that were present after the whole-length protein was cut were themselves toxic.

In their experiments, the authors created transgenic mice that lacked the full-length dystrophin gene, but had a copy of one of two fragments of the gene instead.

If the main problem with cleaving dystrophin was that the full-length protein was not there to fulfill its duties, then mice with the fragments should at least be no worse off than plain dystrophin knockouts.

But if the fragments themselves were toxic, then the transgenic mice with dystrophin fragments should have more heart damage than those with no dystrophin at all.

The team found that having only the C-terminal fragment was indeed worse than having no dystrophin at all.

Further experiments revealed that the problem with the fragment was that it had the same binding partners as dystrophin. As long as more than about half of all dystrophin binding sites were occupied by functional dystrophin, the heart could function more or less normally. But if too many dystrophin binding sites were occupied by the nonfunctional fragment, the animals suffered heart damage including scarring, and were more likely to drop dead from stress.

The results suggested that the cardiac consequences of enterovirus infection might be ameliorated by improving the ratio of full-length dystrophin to the C-terminal fragment. In principle, that ration could be altered in two separate ways: by increasing the amount of full-length dystrophin, possibly via gene therapy, or by speeding up the process by which the fragments are further degraded.

Barnabei said that gene therapy was probably "the most reasonable [option] now," but also noted that "our paper would be at the very beginning of this process."

Where the problem with dystrophin is its cleavage due to viral infection, any replacement protein would also need to be resistant to cleavage to avoid ending up in exactly the same spot, except with higher levels of both full-length dystrophin and the fragment.