Navigation Links
UA researchers find culprit behind skeletal muscle disease

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.


Contact: Shelley Littin
University of Arizona

Related biology news :

1. Researchers tune in to protein pairs
2. Ottawa researchers discover new combination therapy to kill cancer
3. Cleveland Clinic researchers discover process that turns good cholesterol bad
4. Researchers discover potential drug targets for early onset glaucoma
5. Researchers identify innate channel that protects against pain
6. Combustion continues to draw researchers to space station
7. Curtin researchers to hide our splashes from sharks
8. Researchers discover how heart arrhythmia occurs
9. Researchers collaborate to reduce effects of the aging eye
10. 1 step at a time, researchers learning how humans walk
11. Researchers discover that coevolution between humans and bacteria reduces gastric cancer risk
Post Your Comments:
Related Image:
UA researchers find culprit behind skeletal muscle disease
(Date:4/26/2016)... 27, 2016 Research and ... Biometrics Market 2016-2020"  report to their offering.  , ... The analysts forecast the global multimodal biometrics ... during the period 2016-2020.  Multimodal biometrics ... such as the healthcare, BFSI, transportation, automotive, and ...
(Date:4/14/2016)... BioCatch ™, the global ... the appointment of Eyal Goldwerger as CEO. ... Goldwerger,s leadership appointment comes at a time of significant ... of its platform at several of the world,s largest ... unique cognitive and physiological factors, is a winner of ...
(Date:3/29/2016)... , March 29, 2016 LegacyXChange, ... LegacyXChange "LEGX" and SelectaDNA/CSI Protect are pleased to announce ... used in a variety of writing instruments, ensuring athletes ... originally created collectibles from athletes on LegacyXChange will be ... of the DNA. Bill Bollander , ...
Breaking Biology News(10 mins):
(Date:6/24/2016)... ... June 24, 2016 , ... Researchers at the Universita Politecnica delle Marche ... with peritoneal or pleural mesothelioma. Their findings are the subject of a new article ... Diagnostic biomarkers are signposts in the blood, lung fluid or tissue of mesothelioma patients ...
(Date:6/23/2016)... 2016   Boston Biomedical , an industry ... to target cancer stemness pathways, announced that its ... Drug Designation from the U.S. Food and Drug ... including gastroesophageal junction (GEJ) cancer. Napabucasin is an ... cancer stemness pathways by targeting STAT3, and is ...
(Date:6/23/2016)... -- Houston Methodist Willowbrook Hospital has signed a ... serve as their official health care provider. As ... provide sponsorship support, athletic training services, and most ... athletes and families. "We are excited ... to bring Houston Methodist quality services and programs ...
(Date:6/23/2016)... 23, 2016  The Biodesign Challenge (BDC), a university ... to harness living systems and biotechnology, announced its winning ... New York City . ... showcased projects at MoMA,s Celeste Bartos Theater during the ... MoMA,s senior curator of architecture and design, and ...
Breaking Biology Technology: