Aberrant splicing saps the strength of 'slow' muscle fibers

July 29, 2013, Baylor College of Medicine

When you sprint, the "fast" muscle fibers give you that winning kick. In a marathon or just day-to-day activity, however, the "slow," or type 1 fibers, keep you going for hours.

In people with myotonic dystrophy, the second most common form of and the one most likely to occur in adults, these slow or type 1 fibers do not work well, wasting away as the takes its grim toll. In a report that appears online in the Proceedings of the National Academy of Sciences, Dr. Thomas A. Cooper, professor of & immunology at Baylor College of Medicine, and Dr. Zhihua Gao, a postdoctoral associate at BCM, showed how an aberrant alternative splicing program changes the form of an enzyme (pyruvate kinase of PKM) involved in the fundamental metabolism of these cells, leaving them unable to sustain exercise. The enzyme reverts to the embryonic form (PKM2), which changes its activity in the cell.

Alternative splicing is one of the secrets as to how the estimated 25,000 human genes code for the 100,000 or more proteins important to the functioning of the human body. For one gene to make different proteins, it has to alter the genetic message, choosing which coding parts of the gene called exons are included in the protein "recipe" used by the cell's protein-making machinery.

"In the case of PKM2, this enzyme represents a shift back to the fetal splicing pattern," said Cooper. "What was striking was that if you look at the histology (the tissues seen at a microscopic level) of the skeletal muscle, only the slow fiber types – the ones affected in myotonic dystrophy – have this splicing event switch." The slow fibers are those most affected in myotonic dystrophy.

"We don't know what it is doing to the metabolism, but it seems to be pushing it in the opposite direction from what slow fibers do," said Cooper. "This is related to the loss of slow fibers in myotonic dystrophy."

To figure out how this happens, Cooper and his colleagues used antisense oligonucleotides (snippets of genetic material designed to target specific areas of a gene) to bind to the precursor RNA (genetic material that carries the code for a protein) for PKM, and thus force it in the other direction – to the embryonic form.

"Doing this, we showed there could be a change in metabolism in myotonic dystrophy and we showed it in the whole animal," said Cooper.

Myotonic dystrophy occurs when the nucleotides CTG (cytosine, thymine, guanine) repeat an abnormal number of times. When the CTG in the DNA is transcribed into CUG in RNA, the resulting aberrant protein is toxic and disrupts the activity of RNA factors (MBNL1 AND CELF1), which are two RNA splicing factors. The resultant splicing changes somehow drive the skeletal and heart muscle wasting seen in the disease.

"To my knowledge, this is the first time anyone has looked at this alternative splicing event and associated it with a disease other than cancer," said Cooper. "The muscle wasting in this disease could be due to an imbalance of metabolism."

Explore further: Antisense oligonucleotides make sense in myotonic dystrophy

More information: Reexpression of pyruvate kinase M2 in type 1 myofibers correlates with altered glucose metabolism in myotonic dystrophy, www.pnas.org/cgi/doi/10.1073/pnas.1308806110

Related Stories

Antisense oligonucleotides make sense in myotonic dystrophy

February 27, 2012
Antisense oligonucleotides – short segments of genetic material designed to target specific areas of a gene or chromosome – that activated an enzyme to "chew up" toxic RNA (ribonucleic acid) could point the way ...

Scientists turn muscular dystrophy defect on and off in cells

June 28, 2013
For the first time, scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified small molecules that allow for complete control over a genetic defect responsible for the most common adult onset ...

Study sheds light on underlying causes of impaired brain function in muscular dystrophy

August 8, 2012
University of Florida researchers have identified a gene responsible for brain-related symptoms of the most common form of adult-onset muscular dystrophy.

Recommended for you

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

Secrets of longevity protein revealed in new study

January 17, 2018
Named after the Greek goddess who spun the thread of life, Klotho proteins play an important role in the regulation of longevity and metabolism. In a recent Yale-led study, researchers revealed the three-dimensional structure ...

The HLF gene protects blood stem cells by maintaining them in a resting state

January 17, 2018
The HLF gene is necessary for maintaining blood stem cells in a resting state, which is crucial for ensuring normal blood production. This has been shown by a new research study from Lund University in Sweden published in ...

Magnetically applied MicroRNAs could one day help relieve constipation

January 17, 2018
Constipation is an underestimated and debilitating medical issue related to the opioid epidemic. As a growing concern, researchers look to new tools to help patients with this side effect of opioid use and aging.

Researchers devise decoy molecule to block pain where it starts

January 16, 2018
For anyone who has accidentally injured themselves, Dr. Zachary Campbell not only sympathizes, he's developing new ways to blunt pain.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.