Researchers Develop New Stem Cell Based Model of Duchenne Muscular Dystrophy Early Pathogenesis

A study recently published in the journal Scientific Reports reported the development of a novel in vitro model of the early pathogenesis of Duchenne muscular dystrophy (DMD) using stem cells. The study is entitled “Early pathogenesis of Duchenne muscular dystrophy modelled in patient-derived human induced pluripotent stem cells” and was led by researchers at Kyoto University in Japan.

DMD is an inherited disorder caused by a defective gene called dystrophin. It is characterized by a rapid progressive skeletal muscle weakness caused by chronic inflammation and the degeneration of muscle cells and tissue, compromising locomotion and also the respiratory and cardiac function. DMD has a rapid progression and affects mainly boys, with estimates that up to 1 in every 3,500 – 5,000 live male births develops the disease. Most DMD patients require a wheelchair by age 12 and patients often succumb to the disease in their 20s due to respiratory and cardiac failure.

Patient-derived human induced pluripotent stem cells (hiPSCs) are cells with the potential to differentiate into several specialized cell types that represent a promising tool as disease models.

In the study, researchers developed an in vitro model of the initial DMD pathology using intact skeletal myotubes formed from patient-derived hiPSCs. Using their model, researchers found that, different from what was previously thought, DMD myotubes are morphologically and physiologically comparable to normal control myotubes, with a similar growth and differentiation potential. The major difference found was that in DMD myotubes, electric stimulation for in vitro contraction caused a pronounced calcium ion influx, which is seen as an initial trigger for the activation of muscle degenerative pathways in DMD. This phenomenon was not observed in control myotubes.

Interestingly, the team found that by restoring dystrophin expression in DMD myotubes, the calcium overflow was suppressed and the secretion of creatine kinase (a measure of muscle cell damage) reduced.

Researchers concluded that their in vitro system based on patient-derived hiPSCs can recapitulate the early pathogenesis of DMD, and suggest that it could be a valuable tool for the development, screening and evaluation of potential DMD drugs, as well as for the study of the disease pathogenesis. Furthermore, the study reinforces the concept that excessive calcium influx into myotubes under contraction is a primary phenotype of DMD, and demonstrates the importance of a functional dystrophin protein in preventing cellular damage.