Nav: Home

It's how you splice it: Scientists discover possible origin of muscle, heart defects

November 16, 2016

CHAPEL HILL, NC - Muscular dystrophies, congenital heart muscle defects, and other muscle disorders often arise for reasons that scientists don't fully understand. Now researchers from the UNC School of Medicine and Baylor College of Medicine have discovered an important process in muscle cells whose disruption could turn out to be a cause of many of these disorders.

The scientists found that, in mice, four key muscle-cell proteins are produced in a shorter, fetal form up to the first few weeks of life, after which production shifts to longer, adult forms of the proteins. This transition must occur in order for the adult muscle to function normally. Forcing adult muscle cells to produce the shorter, fetal forms leads to major structural problems in the cells and muscle weakness.

"This is the first demonstration that this transition occurs for these proteins in muscle cells and is important for normal muscle function - and it sheds light on the overall functions of these four proteins, about which very little is known," said study co-senior author Jimena Giudice, PhD, a new assistant professor in the department of cell biology and physiology at the UNC School of Medicine.

Thomas Cooper, MD, professor of pathology and immunology at Baylor College of Medicine and study co-senior author, said, "If we are to truly understand the full scope of functions of individual genes, we will need to determine the functions of the different protein isoforms that are generated from each gene. This is particularly important because of the impact that different protein isoforms can have on human health."

Spotlight on alternative splicing

The findings, published in Cell Reports, highlight the biological process known as "alternative splicing," by which a single gene may give rise to multiple forms of a protein.

Normally, when a gene is first transcribed into a strand of RNA, nearby molecular machines grab the raw RNA transcript and slice it into several pieces, which are then spliced back together in alternative ways. Each strand of genetic information then codes for a distinct form (isoform) to create the resulting protein.

Alternative splicing occurs for the vast majority - 90 to 95 percent - of human genes, belying the popular notion that one gene codes for just one protein. The process also occurs for a high percentage of genes in many other animals and even in many plants. Alternative splicing is considered a fundamental amplifier of functional diversity, without which organisms on our planet would be far less complex.

What splice isoform of a protein is produced - or how much of it is produced relative to other isoforms - depends typically on the cell type or the stage of life. For example: fetal versus adult stage. For many genes, this switch in production from one splice isoform to another occurs without any change in the gene's overall transcript-making activity, and thus may not be detected by standard laboratory techniques. Scientists suspect that undiscovered defects in alternative splicing underlie many diseases whose causes have never been identified.

The importance of alternative splicing in muscle cells

Two years ago, in search of such defects, Giudice found that in mouse heart muscle cells, a switch from fetal splice isoforms to adult splice isoforms in the first weeks of life occurs very prominently for some proteins that help maintain healthy cell membranes and for other proteins that help "traffic" molecules to their proper places within these complex cells. She also found that forcing the heart muscle cells of adult mice to return to producing fetal isoforms of these proteins, not the adult isoforms, leads to significant abnormalities in the cells. This work was part of Giudice's postdoctoral training in Cooper's lab at Baylor.

In the new study, Giudice and colleagues discovered that four of these proteins important for membrane dynamics and molecular trafficking also undergo a splicing transition in the first weeks of life in cells that make up skeletal muscles - the muscles of arms and legs, for example. To investigate the importance of this transition, the scientists this time used a more tightly targeted technique to force (in the foot muscles of adult mice) the production of the fetal-stage isoforms, which are shorter than their adult counterparts.

The scientists found that once these adult muscle cells reverted to producing the shorter, fetal isoforms of the proteins, the muscles became much weaker. The muscle cells themselves also had major disruptions to their internal structures.

"Certain molecules that are very important for muscle contraction and the generation of force were no longer where they should be within those muscle cells, for example," said Giudice, who is also a member of the McAllister Heart Institute and part of the Curriculum in Genetics & Molecular Biology at UNC.

Cooper added, "This work is the first to show in muscle cell tissue that the different protein isoforms expressed from one and likely more of these four genes has a specific role in the remodeling of skeletal muscle from fetal to adult function."

Previous studies linked some skeletal muscle and heart muscle disorders to mutations of trafficking and membrane dynamics genes. This work suggested that the corresponding proteins are generally very important for muscle health. The new findings hint that such proteins may contribute to muscle disorders not just by being absent or grossly altered by gene defects, but also by the relatively subtle failure to switch to the proper protein isoform in cellular adulthood.

Giudice and her colleagues are now trying to uncover the details of the muscle-cell signaling pathways that are disrupted when fetal forms of these proteins are produced in adults. They hope that understanding how those disrupted pathways lead to muscle defects will shed light on the causes of a variety of human muscle disorders.
-end-
Giudice completed the study as a faculty member at UNC but began it while working as a postdoctoral researcher in the laboratory of Thomas A. Cooper, MD, professor of pathology and immunology at Baylor College of Medicine. Cooper was co-senior author for the study. The other co-authors were Baylor graduate student James A. Loehr and Baylor associate professor George G. Rodney, PhD.

The National Institutes of Health, the American Heart Association, and the U.S. Public Health Service funded this research.

University of North Carolina Health Care

Related Proteins Articles:

Discovering, counting, cataloguing proteins
Scientists describe a well-defined mitochondrial proteome in baker's yeast.
Interrogating proteins
Scientists from the University of Bristol have designed a new protein structure, and are using it to understand how protein structures are stabilized.
Ancient proteins studied in detail
How did protein interactions arise and how have they developed?
What can we learn from dinosaur proteins?
Researchers recently confirmed it is possible to extract proteins from 80-million-year-old dinosaur bones.
Relocation of proteins with a new nanobody tool
Researchers at the Biozentrum of the University of Basel have developed a new method by which proteins can be transported to a new location in a cell.
Proteins that can take the heat
Ancient proteins may offer clues on how to engineer proteins that can withstand the high temperatures required in industrial applications, according to new research published in the Proceedings of the National Academy of Sciences.
Designer proteins fold DNA
Florian Praetorius and Professor Hendrik Dietz of the Technical University of Munich have developed a new method that can be used to construct custom hybrid structures using DNA and proteins.
The proteins that domesticated our genomes
EPFL scientists have carried out a genomic and evolutionary study of a large and enigmatic family of human proteins, to demonstrate that it is responsible for harnessing the millions of transposable elements in the human genome.
Rare proteins collapse earlier
Some organisms are able to survive in hot springs, while others can only live at mild temperatures because their proteins aren't able to withstand such extreme heat.
How proteins reshape cell membranes
Small 'bubbles' frequently form on membranes of cells and are taken up into their interior.

Related Proteins Reading:

The High-Protein Vegetarian Cookbook: Hearty Dishes that Even Carnivores Will Love
by Katie Parker (Author), Kristen Smith (Author)

Proteins: Structure and Function
by David Whitford (Author)

Proteins: Concepts in Biochemistry
by Paulo Almeida (Author)

The High-Protein Cookbook: More than 150 healthy and irresistibly good low-carb dishes that can be on the table in thirty minutes or less.
by Linda West Eckhardt (Author), Katherine West Defoyd (Author)

Protein Power: The High-Protein/Low Carbohydrate Way to Lose Weight, Feel Fit, and Boost Your Health-in Just Weeks!
by Michael R. Eades (Author), Mary Dan Eades (Author)

The Ultimate Protein Powder Cookbook: Think Outside the Shake (New format and design)
by Anna Sward (Author)

Plant-Protein Recipes That You'll Love: Enjoy the goodness and deliciousness of 150+ healthy plant-protein recipes!
by Carina Wolff (Author)

Janeva's Ideal Recipes: A Personal Recipe Collection for the Ideal Protein Phase 1 Diet [Revised Version 1]
by Janeva Caroline Eickhoff (Author)

The Oil-Protein Diet Cookbook
by Johanna Budwig (Author)

High-Protein Shakes: Strength-Building Recipes for Everyday Health
by Pamela Braun (Author)

Best Science Podcasts 2018

We have hand picked the best science podcasts for 2018. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Circular
We're told if the economy is growing, and if we keep producing, that's a good thing. But at what cost? This hour, TED speakers explore circular systems that regenerate and re-use what we already have. Guests include economist Kate Raworth, environmental activist Tristram Stuart, landscape architect Kate Orff, entrepreneur David Katz, and graphic designer Jessi Arrington.
Now Playing: Science for the People

#504 The Art of Logic
How can mathematics help us have better arguments? This week we spend the hour with "The Art of Logic in an Illogical World" author, mathematician Eugenia Cheng, as she makes her case that the logic of mathematics can combine with emotional resonance to allow us to have better debates and arguments. Along the way we learn a lot about rigorous logic using arguments you're probably having every day, while also learning a lot about our own underlying beliefs and assumptions.