Nav: Home

Multiple mechanisms behind disease associated with unexpected heart attacks

April 04, 2019

TROY, N.Y. --Hypertrophic cardiomyopathy is best known for revealing itself in one certain way: as an unexpected, fatal heart attack during strenuous exercise. But researchers suspect as many as 300 mutations can individually cause enlargement of the heart that renders it vulnerable to strain. Recent studies examining three of those mutations at the molecular level found separate mechanisms at work, said Rensselaer Polytechnic Institute muscle protein and contraction expert Doug Swank, whose most recent paper on the topic was published today in the Journal of Physiology.

"Our work suggests that a simple one-size-fits-all hypothesis about how these mutations lead to an enlarged heart and to the disease is not likely to be the case. It's likely to be multiple mechanisms, perhaps depending on where the mutation is found in the protein or what it does to the protein," said Swank, a professor of biological sciences and member of the Rensselaer Center for Biotechnology and Interdisciplinary Studies.

Swank's research on hypertrophic cardiomyopathy is being conducted in collaboration with researchers at San Diego State University and Johns Hopkins University, with support from the National Institutes of Health.

The current paper and a previous study published in eLife in 2018 examine two mutations in myosin, a lever-shaped muscle protein that generates force to contract heart muscle tissue. Like all proteins, muscle proteins are chains of amino acids twisted into a three-dimensional shape that determines their function. But mutations slightly alter the composition of the amino acid chain, which also changes the shape of the protein and its performance.

Swanks' lab expresses the mutation in the wing muscle of a fruit fly, making it possible to examine how the mutations impact mechanical properties like force production, work and power. The eLife study looked at a mutation in myosin known as K146N (the mutation name is derived from the name of the affected amino acid residue and how it is altered in myosin). Examinations of fruit fly muscles with this mutation supported the "increased contractility hypothesis," which proposes that the heart is spending more time in a contracted state than in a relaxed state.

Ordinarily, as filaments of the myosin protein absorb energy, they bind to filaments of the protein actin and bend back upon themselves, pulling on the actin filaments and contracting the muscle.

"Our results for K146N indicated that the myosin bound longer to actin than it normally does," said Swank. "Considering that hundreds of these myosin molecules are doing this all the time, if they stay bound longer, at any given time you're going to have more myosin heads bound and pulling together than you otherwise would. So that gives you more force."

But the newly released Journal of Physiology study looked at an R249Q mutation and found a nearly opposite result. Fruit fly muscle with a R249Q mutation, which typically produces a less severe form of the disease, generated less force, less work, and less power. Swank said this result suggests that, in the heart, such a mutation is unlikely to be causing increased contractility - and yet it yields a similar outcome.

A third study to be published in the near future describes a mechanism for a mutation in another heart protein.

"Our hope is that, as we continue to understand how these mutations affect muscle contraction, a few general mechanisms will emerge which will make it possible to devise a group of treatments to address the disease," said Swank.
-end-
Swank, Rensselaer graduate student Kaylyn Bell, and undergraduate student Alice Huang were joined by San Diego State University researchers William A. Kronert and Sanford Bernstein on "The R249Q Hypertrophic Cardiomyopathy Mutation Decreases Contractility in Drosophila by Impeding Force Production," published in the Journal of Physiology.

About Rensselaer Polytechnic Institute

Founded in 1824, Rensselaer Polytechnic Institute is America's first technological research university. Rensselaer encompasses five schools, 32 research centers, more than 145 academic programs, and a dynamic community made up of more than 7,900 students and over 100,000 living alumni. Rensselaer faculty and alumni include more than 145 National Academy members, six members of the National Inventors Hall of Fame, six National Medal of Technology winners, five National Medal of Science winners, and a Nobel Prize winner in Physics. With nearly 200 years of experience advancing scientific and technological knowledge, Rensselaer remains focused on addressing global challenges with a spirit of ingenuity and collaboration. To learn more, please visit http://www.rpi.edu.

Rensselaer Polytechnic Institute

Related Protein Articles:

Discovery of an unusual protein
Scientists from Bremen discover an unusual protein playing a significant role in the Earth's nitrogen cycle.
Protein aggregation: Protein assemblies relevant not only for neurodegenerative disease
Amyloid fibrils play a crucial role in neurodegenerative illnesses. Scientists from Heinrich Heine University Düsseldorf (HHU) and Forschungszentrum Jülich have now been able to use cryo-electron microscopy (cryo-EM) to decode the spatial structure of the fibrils that are formed from PI3K SH3 domains - an important model system for research.
Old protein, new tricks: UMD connects a protein to antibody immunity for the first time
How can a protein be a major contributor in the development of birth defects, and also hold the potential to provide symptom relief from autoimmune diseases like lupus?
Infection-fighting protein also senses protein misfolding in non-infected cells
Researchers at the University of Toronto have uncovered an immune mechanism by which host cells combat bacterial infection, and at the same time found that a protein crucial to that process can sense and respond to misfolded proteins in all mammalian cells.
Quorn protein builds muscle better than milk protein
A study from the University of Exeter has found that mycoprotein, the protein-rich food source that is unique to Quorn products, stimulates post-exercise muscle building to a greater extent than milk protein.
More than a protein factory
Researchers from the Stowers Institute for Medical Research have discovered a new function of ribosomes in human cells that may show the protein-making particle's role in destroying healthy mRNAs, the messages that decode DNA into protein.
Put down the protein shake: Variety of protein better for health
University of Sydney researchers have examined whether there are any ongoing ramifications or potential side-effects from long-term high protein intake or from consuming certain types of amino acids.
Elucidating protein-protein interactions & designing small molecule inhibitors
To carry out wide range of cellular functionalities, proteins often associate with one or more proteins in a phenomenon known as Protein-Protein Interaction (PPI).
The protein with the starting gun
Whether dormant bacteria begin to reproduce is no accident. Rather, they are simply waiting for a clear signal from a single protein in the cell interior.
Protein moonlighting
A class of proteins involved in essential cell functions has an unexpected role, UCSB scientists discover.
More Protein News and Protein Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

In & Out Of Love
We think of love as a mysterious, unknowable force. Something that happens to us. But what if we could control it? This hour, TED speakers on whether we can decide to fall in — and out of — love. Guests include writer Mandy Len Catron, biological anthropologist Helen Fisher, musician Dessa, One Love CEO Katie Hood, and psychologist Guy Winch.
Now Playing: Science for the People

#543 Give a Nerd a Gift
Yup, you guessed it... it's Science for the People's annual holiday episode that helps you figure out what sciency books and gifts to get that special nerd on your list. Or maybe you're looking to build up your reading list for the holiday break and a geeky Christmas sweater to wear to an upcoming party. Returning are pop-science power-readers John Dupuis and Joanne Manaster to dish on the best science books they read this past year. And Rachelle Saunders and Bethany Brookshire squee in delight over some truly delightful science-themed non-book objects for those whose bookshelves are already full. Since...
Now Playing: Radiolab

An Announcement from Radiolab