Healthy muscle cells express dystrophin (green, left), but DMD patients do not (middle). Treating iPS cells that are then differentiated into muscle cells can recover dystrophin levels (right). [Dr. Hidetoshi Sakurai Laboratory, Kyoto University]
Healthy muscle cells express dystrophin (green, left), but DMD patients do not (middle). Treating iPS cells that are then differentiated into muscle cells can recover dystrophin levels (right). [Dr. Hidetoshi Sakurai Laboratory, Kyoto University]

Duchenne muscular dystrophy (DMD) is a rapidly progressive degenerative muscle disease that occurs primarily in boys, affecting approximately 1 in 3,500 male births worldwide. The disease is caused by a mutation in the dystrophin gene, which typically codes for a protein that helps keep muscle cells intact. The mutation often leads to a complete loss of the protein and is inherited through families in an X-linked recessive fashion.

Due to poor understanding of how DMD develops, there are few treatment options. Yet, new evidence from researchers at the Center for IPS Cell Research and Application in collaboration with the Institute for Frontier Medical Sciences, both at Kyoto University, may help to explain how DMD progresses and provide valuable targets for therapeutic intervention.  

The researchers isolated fibroblasts from DMD patients and reprogrammed them to become induced pluripotent stem (iPS) cells. The iPS cells were then introduced to a master regulator gene that differentiated them into developing muscle cells, or myotubes.    

“Our model allows us to use the same genetic background to study the early stage of pathogenesis which was not possible in the past,” explained lead author Emi Shoji, researcher at CiRA.  

The findings from this study were published recently in Scientific Reports through an article entitled “Early pathogenesis of Duchenne muscular dystrophy modelled in patient-derived human induced pluripotent stem cells.”

“In this study, we established a novel evaluation system to analyze the cellular basis of early DMD pathogenesis by comparing DMD myotubes with the same clone but with truncated dystrophin-expressing DMD myotubes,” wrote the scientists.

Since muscle contraction depends on the influx of calcium ions (Ca2+) into the cells the researchers decided to look at the ion channels that regulate the flow calcium in the differentiated myotubes.

“It is critical to assess intact cells for an accurate evaluation how Ca2+ influx leads to DMD pathogenic cascades,” noted Shoji.

The scientists observed that after electrical stimulation, the DMD differentiated myotubes had a significantly increased influx of Ca2+, which led to cell dysfunction and death. Further study revealed that the transient receptor potential (TRP) channels through which the Ca2+ ions enter the cell were the real cause of the aberrant ion influx.  

“TRP channels have been identified before, but because our model uses patient-derived hiPS cells, there is a potential that we can find new drugs for DMD,” stated senior author Hidetoshi Sakurai, M.D., Ph.D., senior lecturer at the CiRA.

The researchers plan to continue their work trying to identify all of the molecular mechanisms surrounding this new finding. Furthermore, extended their work to even more DMD patients could uncover new contributing mutations that have been over in this disease.

“These results suggest that the early pathogenesis of DMD can be recapitulated with our system utilizing hiPSCs. Moreover, this system may enable the development of effective drugs that are applicable for most genetic variants of DMD by phenotypic screening based on early pathogenesis,” the investigators concluded.

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