Fast muscle fibers are helpful in maintaining fast but strong muscular contractions that are responsible for locomotion and other day-to-day activities; however, slow fibers are needed for activities that require sustained muscular contractions for hours. Myotonic muscular dystrophy is referred to as the second most common form of muscular dystrophy in adults that primarily affects slow or type 1 fibers. With advanced disease, muscle fibers are generally wasted, leading to weaker contractions.
The results of the research report were published online in the Proceedings of the National Academy of Sciences. Researchers from Baylor College of Medicine Dr. Thomas A. Cooper (who is also a professor of pathology & immunology at Baylor College of Medicine) and Dr. Zhihua Gao, a postdoctoral associate at BCM, explained the mechanism of aberrant alternative splicing that affects the functioning of enzymes (pyruvate kinase or PKM). PKM is an essential enzyme that takes part in the fundamental metabolism of slow muscle cells, responsible for sustained muscle activity. The phenomenon of aberrant alternative splicing converts the enzyme to the embryonic form (PKM2), which changes the function and activity of enzyme in the cell.
What is alternative splicing?
One of the cellular secrets that explain how 25,000 human genes have the capability to code for over 100,000 proteins is alternative splicing. One gene can code for different vital proteins responsible for cellular functions by altering the genetic message.
“In the case of PKM2, this enzyme represents a shift back to the fetal splicing pattern. 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.”
Muscular dystrophy affects the metabolism and functioning of slow fibers the most. Cooper further added:
“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. This is related to the loss of slow fibers in myotonic dystrophy.”
The study by Baylor College of Medicine researchers:
Cooper and his colleagues from Baylor College of Medicine utilized antisense oligonucleotides to study the metabolism of PKM. Oligonucleotides are the snippets of genetic material that is programmed to target designated areas of gene. Cooper binds the oligonucleotides to the precursor RNA (or the genetic code for a protein) for PKM, thereby forcing it 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.”
“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. The muscle wasting in this disease could be due to an imbalance of metabolism.”
The researchers concluded that the abnormal repetition of nucleotides CTG (cytosine, thymine, guanine) leads to Myotonic dystrophy. The CTG of DNA is transcribed to CUG of RNA, to produce the aberrant, toxic protein that is capable of disrupting the functioning of RNA splicing factors (MBNL1 AND CELF1), As a result of the splicing changes, the metabolism of muscles is significantly affected leading to pre-mature wasting of heart and skeletal muscles.
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