Nav: Home

Micropeptide restores heart function in mice

October 09, 2018

Researchers have discovered a micropeptide molecule that can restore normal heart function in mice, according to a study in eLife.

The micropeptide works by preventing calcium dysregulation and remodelling of the heart and could be a promising new gene therapy target to treat heart failure.

Among the many processes that lead to heart failure, the disruption caused by calcium is the most prominent. The movement of calcium in and out of cells - known as calcium cycling - is the vital process that allows the heart muscle to contract and relax, pumping blood around the body. Relaxation is controlled by a calcium pump called SERCA, but the action of this molecule is impaired in heart failure and it has previously been suggested that boosting the activity of SERCA could preserve heart contractility and treat heart failure.

"Our lab recently discovered a micropeptide called Dwarf Open Reading Frame (DWORF), which binds directly to SERCA and enhances its activity," explains lead author Catherine Makarewich, postdoctoral researcher at the University of Texas Southwestern Medical Center, US. "In this study, we explored the therapeutic potential of high levels of DWORF, as a way to increase SERCA activity and improve heart contractility in heart failure."

The team's previous work suggested that DWORF works by displacing a molecule that inhibits SERCA, called phospholamban (PLN). To investigate this further, they engineered mice to have higher levels of DWORF and/or PLN in the heart and then studied the effects.

They found that the engineered mice and normal mice had similar cardiac function and structure, but the mice engineered to have higher levels of DWORF showed enhanced calcium cycling. Conversely, heart muscle cells from the mice with higher levels of PLN showed the opposite and had reduced contractility. In the mice engineered to have high levels of both DWORF and PLN, the adverse effects of excess PLN were completely prevented, suggesting that DWORF could protect against its pathological activity.

To investigate this further, the team looked at the effects of increasing the levels of DWORF in mice with dilated cardiomyopathy - a condition in which the heart becomes large and cannot pump properly. When studied by echocardiography, the mice with cardiomyopathy had reduced contraction power in the left ventricle of the heart as shown by a lower ejection fraction (the amount of blood ejected from the heart chamber with each contraction). By contrast, the mice with higher levels of DWORF had significantly improved left ventricular function. Mice that had DWORF removed entirely had even more of a decline in heat function than the normal mice with cardiomyopathy.

High levels of DWORF also prevented the physical hallmarks of cardiomyopathy in the mice - the enlargement of heart chambers, thinning of the chamber wall, and increase in the volume of heart muscle cells. The build-up of scar tissue in the heart is also characteristic of myopathy, and this was also prevented in the mice with elevated levels of DWORF. Taken together, the results show that DWORF can prevent both the functional and structural effects of cardiomyopathy in mice.

"Previous attempts to restore SERCA to protect against heart failure have been unsuccessful because they have focused on increasing levels of SERCA itself," explains senior author Eric Olson, Professor in Stem Cell Research at UT Southwestern Medical Center. "We believe that increasing levels of DWORF instead may be more feasible, and that the small size of the DWORF molecule could make it an attractive candidate for a gene therapy drug for heart failure."
-end-
Reference

The paper 'The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy' can be freely accessed online at https://doi.org/10.7554/eLife.38319. Contents, including text, figures and data, are free to reuse under a CC BY 4.0 license.

Media contact

Emily Packer, Senior Press Officer
eLife
e.packer@elifesciences.org
01223 855373

About eLife

eLife aims to help scientists accelerate discovery by operating a platform for research communication that encourages and recognises the most responsible behaviours in science. We publish important research in all areas of the life and biomedical sciences, including Cell Biology, which is selected and evaluated by working scientists and made freely available online without delay. eLife also invests in innovation through open source tool development to accelerate research communication and discovery. Our work is guided by the communities we serve. eLife is supported by the Howard Hughes Medical Institute, the Max Planck Society, the Wellcome Trust and the Knut and Alice Wallenberg Foundation. Learn more at https://elifesciences.org/about.

To read the latest Cell Biology research published in eLife, please visit https://elifesciences.org/subjects/cell-biology.

eLife

Related Heart Failure Articles:

Heart attacks, heart failure, stroke: COVID-19's dangerous cardiovascular complications
A new guide from emergency medicine doctors details the potentially deadly cardiovascular complications COVID-19 can cause.
Autoimmunity-associated heart dilation tied to heart-failure risk in type 1 diabetes
In people with type 1 diabetes without known cardiovascular disease, the presence of autoantibodies against heart muscle proteins was associated with cardiac magnetic resonance (CMR) imaging evidence of increased volume of the left ventricle (the heart's main pumping chamber), increased muscle mass, and reduced pumping function (ejection fraction), features that are associated with higher risk of failure in the general population
Transcendental Meditation prevents abnormal enlargement of the heart, reduces chronic heart failure
A randomized controlled study recently published in the Hypertension issue of Ethnicity & Disease found the Transcendental Meditation (TM) technique helps prevent abnormal enlargement of the heart compared to health education (HE) controls.
Beta blocker use identified as hospitalization risk factor in 'stiff heart' heart failure
A new study links the use of beta-blockers to heart failure hospitalizations among those with the common 'stiff heart' heart failure subtype.
Type 2 diabetes may affect heart structure and increase complications and death among heart failure patients of Asian ethnicity
The combination of heart failure and Type 2 diabetes can lead to structural changes in the heart, poorer quality of life and increased risk of death, according to a multi-country study in Asia.
Preventive drug therapy may increase right-sided heart failure risk in patients who receive heart devices
Patients treated preemptively with drugs to reduce the risk of right-sided heart failure after heart device implantation may experience the opposite effect and develop heart failure and post-operative bleeding more often than patients not receiving the drugs.
How the enzyme lipoxygenase drives heart failure after heart attacks
Heart failure after a heart attack is a global epidemic leading to heart failure pathology.
Novel heart pump shows superior outcomes in advanced heart failure
Severely ill patients with advanced heart failure who received a novel heart pump -- the HeartMate 3 left ventricular assist device (LVAD) -- suffered significantly fewer strokes, pump-related blood clots and bleeding episodes after two years, compared with similar patients who received an older, more established pump, according to research presented at the American College of Cardiology's 68th Annual Scientific Session.
NSAID impairs immune response in heart failure, worsens heart and kidney damage
Non-steroidal anti-inflammatory drugs, or NSAIDs, are widely known as pain-killers and can relieve pain and inflammation.
Heart cell defect identified as possible cause of heart failure in pregnancy
A new Tel Aviv University study reveals that one of the possible primary causes of heart failure in pregnant women is a functional heart cell defect.
More Heart Failure News and Heart Failure Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Processing The Pandemic
Between the pandemic and America's reckoning with racism and police brutality, many of us are anxious, angry, and depressed. This hour, TED Fellow and writer Laurel Braitman helps us process it all.
Now Playing: Science for the People

#568 Poker Face Psychology
Anyone who's seen pop culture depictions of poker might think statistics and math is the only way to get ahead. But no, there's psychology too. Author Maria Konnikova took her Ph.D. in psychology to the poker table, and turned out to be good. So good, she went pro in poker, and learned all about her own biases on the way. We're talking about her new book "The Biggest Bluff: How I Learned to Pay Attention, Master Myself, and Win".
Now Playing: Radiolab

Invisible Allies
As scientists have been scrambling to find new and better ways to treat covid-19, they've come across some unexpected allies. Invisible and primordial, these protectors have been with us all along. And they just might help us to better weather this viral storm. To kick things off, we travel through time from a homeless shelter to a military hospital, pondering the pandemic-fighting power of the sun. And then, we dive deep into the periodic table to look at how a simple element might actually be a microbe's biggest foe. This episode was reported by Simon Adler and Molly Webster, and produced by Annie McEwen and Pat Walters. Support Radiolab today at Radiolab.org/donate.