Credit: ©Mark Strozier

The discovery of small RNA molecules that affect gene expression is one of the watershed developments in molecular biology, but relatively little is known about how these bits of RNA function, especially in higher vertebrates. Now, for the first time in mammals, researchers have identified consequences associated with the deletion of one of these RNA molecules.

MicroRNAs (miRNAs) are short pieces of RNA that do not code for proteins. Complex cellular machinery uses miRNAs to degrade or inhibit the translation of specific sequences of mRNA, preventing the synthesis of corresponding proteins. In early experiments, Eva van Rooij and Eric N. Olson, researchers at the University of Texas-Southwestern Medical Center (Dallas), found that certain miRNAs increased or decreased in cardiac tissue in response to heart stress.

One of these miRNAs, miR-208, is located in an untranslated region of the gene for the alpha myosin heavy chain (αMHC). αMHC, along with its cousin βMHC, are cardiac proteins responsible for the heart's most characteristic feature: its beat. In the adult human heart, the right ratio of βMHC to αMHC is essential for optimum cardiac output, but studies have shown that heart stress throws off that balance by increasing the relative abundance of βMHC to αMHC, resulting in poor cardiac performance.

van Rooij and her colleagues decided to knock out the gene for miR-208 in mice to better understand its effects. After deleting the gene, the researchers exposed both mutant and wildtype mice to cardiac stress and found that the mutants did not increase in cardiac βMHC and did not display the characteristic pathological changes seen in the hearts of wildtype mice, evidence that miR-208 regulates βMHC expression (Science, doi: 10.1126/science.1139089, published online 22 March).

Ideally, these findings will be applicable to humans and provide a way to shield people from heart damage—perhaps by selectively suppressing miR-208 expression and thereby maintaining the ideal α- to βMHC ratio. Still, baseline differences in MHC composition of human and rodent hearts may present obstacles to clinical therapy. “Since the MHC composition differs at baseline in humans [and mice],” van Rooij tells Lab Animal, “it might be very meaningful to determine whether the regulation of the βMHC levels by miR-208 can be recapitulated in larger animal models, like rabbits, in which the baseline α- and βMHC levels are more comparable to the human system.”