Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

UA Researchers Find Culprit Behind Skeletal Muscle Disease

29.01.2014
A University of Arizona doctoral candidate has shown for the first time that genetic mutations in the titin gene can cause skeletal muscle myopathy, a disease in which muscle fibers do not function properly, resulting in muscle weakness. Myopathic disease can affect heart muscles as well as skeletal muscles, and titin is responsible for many problems associated with heart disease.

The research was done by Danielle Buck, a doctoral candidate in the UA’s Department of Molecular and Cellular Biology. She worked under the direction of Henk Granzier, a professor in cellular and molecular medicine and physiology, who has studied titin for years.

Previous studies had shown that alterations in titin are involved in muscular myopathies, but whether these deviations actually cause myopathies, or merely result from them, has remained a mystery.

Buck has shown that mutations in the titin gene do in fact cause myopathies in skeletal muscles. Her study, published today in the Journal of General Physiology, could be an important first step in developing treatments to address causes of the disease.

“Patients with muscle myopathy experience muscle weakness, but not a lot has been known about what is going wrong at the molecular and genetic level, except that titin is often involved,” Buck said. “Many patients with heart disease also have mutations in titin. So to develop treatments we need to understand the structure of titin and how it can cause or respond to disease.”

“With about 35,000 amino acids, titin is the largest protein known, roughly 100 times larger than typical proteins, which have only around several hundred amino acids,” Granzier explained. Amino acids are the building blocks of proteins.

Titin, he said, functions as a molecular spring that makes tissues elastic so that when they deform they can snap back again. “Titin is a vital determinant of the elasticity of skeletal and heart muscles, which is very important for normal muscular function,” he noted.

“Titin is like the stretchy material in a rubber balloon,” said Buck. “If you have a balloon that is too stretchy or too stiff, then it’s not going to be able to expand or contract. Tissues also need to have elasticity so that they can restore their original shape after they have been contracted.”

Conducting genetic testing for mutations in the titin gene and studying the defects in the protein have been challenging due to titin’s “enormous size,” Granzier said. “But excellent facilities at the University of Arizona have enabled researchers to make great impact and progress has recently accelerated.”

Buck’s research “has directly shown that introducing specific changes to the titin gene can lead to disease in skeletal muscles,” Granzier said. “We know now that titin itself can trigger the disease. Danielle’s research shows that this giant protein needs to be tuned just right or it can cause myopathies to develop in skeletal muscles.”

Buck’s research “also demonstrated for the first time that changing a part of the gene results in a cascade of additional damaging changes in the protein,” he added.

“We found that in skeletal muscles, deleting one area of titin can affect expression of the entire protein and other areas can subsequently be deleted as well,” Buck said. “Shortening titin leads to a cascade of effects that cause titin to be even shorter, and that causes the muscle to become very stiff.”

Buck approached her work from many levels, Granzier said. “She worked at the gene level, the transcription level, the protein level and the functional level of cells and tissues to get an integrative understanding of the changes that this genetic modification caused.”

“We try to look at all these levels so that we can get a deeper understanding of the mechanisms that give rise to disease,” he added. “It is a multidisciplinary study, from molecular and cellular biology to integrative physiology.”

Understanding what factors cause myopathies could enable researchers to reverse the disease in humans by developing medications to counter damaging activity of the gene, Buck said.

“The next step ideally would be to use this model as an avenue to find new future therapeutic targets,” she said.

Buck already has begun to forge into research around a possible cure for myopathies.

Granzier’s lab, including John Smith and Charles Chung, collaborated with researchers at the Tokyo Metropolitan Institute of Medical Science in Japan and at the University of Heidelberg in Germany. The study was supported by National Institutes of Health grants to Granzier as well as fellowships from the Bellows Foundation and the ARCS Foundation to Buck.

This story and photos are online:
http://uanews.org/story/ua-researchers-find-culprit-behind-skeletal-muscle-disease

Research paper: http://jgp.rupress.org/content/143/2/215

Contacts

Sources
Henk Granzier
Professor, Molecular and Cellular Biology and Physiology
520-626-3641
granzier@email.arizona.edu
Danielle Buck
Doctoral candidate, Molecular and Cellular Biology
dbuck1@email.arizona.edu
UANews Contact
Shelley Littin
319-541-1482
littin@email.arizona.edu

Shelley Littin | UANews
Further information:
http://www.arizona.edu

More articles from Health and Medicine:

nachricht Antibiotic effectiveness imperiled as use in livestock expected to increase
27.03.2015 | Princeton University

nachricht A human respiratory tissue model to assess the toxicity of inhaled chemicals and pollutants
26.03.2015 | R&D at British American Tobacco

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Experiment Provides the Best Look Yet at 'Warm Dense Matter' at Cores of Giant Planets

In an experiment at the Department of Energy's SLAC National Accelerator Laboratory, scientists precisely measured the temperature and structure of aluminum as...

Im Focus: Energy-autonomous and wireless monitoring protects marine gearboxes

The IPH presents a solution at HANNOVER MESSE 2015 to make ship traffic more reliable while decreasing the maintenance costs at the same time. In cooperation with project partners, the research institute from Hannover, Germany, has developed a sensor system which continuously monitors the condition of the marine gearbox, thus preventing breakdowns. Special feature: the monitoring system works wirelessly and energy-autonomously. The required electrical power is generated where it is needed – directly at the sensor.

As well as cars need to be certified regularly (in Germany by the TÜV – Technical Inspection Association), ships need to be inspected – if the powertrain stops...

Im Focus: 3-D satellite, GPS earthquake maps isolate impacts in real time

Method produced by UI researcher could improve reaction time to deadly, expensive quakes

When an earthquake hits, the faster first responders can get to an impacted area, the more likely infrastructure--and lives--can be saved.

Im Focus: Atlantic Ocean overturning found to slow down already today

The Atlantic overturning is one of Earth’s most important heat transport systems, pumping warm water northwards and cold water southwards. Also known as the Gulf Stream system, it is responsible for the mild climate in northwestern Europe. 

Scientists now found evidence for a slowdown of the overturning – multiple lines of observation suggest that in recent decades, the current system has been...

Im Focus: Robot inspects concrete garage floors and bridge roadways for damage

Because they are regularly subjected to heavy vehicle traffic, emissions, moisture and salt, above- and underground parking garages, as well as bridges, frequently experience large areas of corrosion. Most inspection systems to date have only been capable of inspecting smaller surface areas.

From April 13 to April 17 at the Hannover Messe (hall 2, exhibit booth C16), engineers from the Fraunhofer Institute for Nondestructive Testing IZFP will be...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

World Conference On Regenerative Medicine 2015: Registration And Abstract Submission Now Open

25.03.2015 | Event News

University presidents from all over the world meet in Hamburg

19.03.2015 | Event News

10. CeBiTec Symposium zum Big Data-Problem

17.03.2015 | Event News

 
Latest News

Two Most Destructive Termite Species Forming Superswarms in South Florida

27.03.2015 | Agricultural and Forestry Science

ORNL-Led Team Demonstrates Desalination with Nanoporous Graphene Membrane

27.03.2015 | Materials Sciences

Coorong Fish Hedge Their Bets for Survival

27.03.2015 | Ecology, The Environment and Conservation

VideoLinks
B2B-VideoLinks
More VideoLinks >>>