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UT Southwestern Team Finds ncRNA-Encoded Peptide Involved in Heart Contraction

NEW YORK (GenomeWeb) – A group of University of Texas Southwestern Medical Center researchers have reported the discovery of a peptide expressed from a long, non-coding RNA that appears to play an important role in the heart's ability to contract.

The findings, which appeared last week in Science, not only points to a potential new drug target for treating heart failure, but also suggests that there may be other ncRNA-derived peptides with critical biological functions that have yet to be found.

The study was led by UTSWMC's Eric Olson, whose lab has long focused on the genetics of muscle cell formation and function, as well as the roles of non-coding RNAs such as lncRNAs and microRNAs in heart development and disease. As part of that work, Olson and his colleagues discovered a putative muscle-specific lncRNA that encodes a short peptide — just 34 amino acids long — that localizes to the membrane of the sarcoplasmic reticulum (SR), which is the endoplasmic reticulum found in myocytes and is closely involved in regulating muscle contractions. Specifically, the team found, when muscle cells are activated by electrical stimulation, calcium ions are released from the SR triggering muscle contraction. The SR reabsorbs the ions during muscle relaxation.

The peptide was found to enhance the activity of the Ca2+ adenosine triphosphatase SERCA, which handles the flow of calcium ions in and out of the SR, by displacing key SERCA inhibitors. When the peptide, called Dworf, was overexpressed in the cardiomyocytes of mice, SR calcium ion uptake was enhanced and the animals' hearts pumped blood with greater force.

"There's a brake in the heart that controls pumping, and Dworf shuts off the brake, which has the effect of making heart muscle pump more vigorously," Olson said in a statement.

The scientists also identified Dworf in certain skeletal muscle cells including slow-twitch muscle fibers in mice (although not at the same high levels as in cardiac muscle cells) and found that its suppression in these cells leads to delayed clearance of calcium ions and muscle relaxation, as well as reduced SERCA activity.

Taken together, the data point to the potential of Dworf as a target for treating the poor heart contractility that is one of the hallmarks of congestive heart failure. 

"Our results underscore the likelihood that many transcripts currently annotated as non-coding RNAs encode peptides with important biological functions," Olson and his group wrote in Science. "These small peptides may evolve rapidly as singular functional domains that fine-tune the activities of larger preexisting molecular complexes, rather than having intrinsic biologic effects themselves. In this regard, small peptides may be uniquely suited to act as key factors in evolutionary adaptation and speciation."

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