Type 1 ryanodine receptor (RYR1)-mediated intracellular calcium (Ca2+) leakage seems to play a key role in the impairment of myogenic differentiation in Duchenne muscular dystrophy (DMD), according to a new study published in the International Journal of Molecular Sciences.
Therefore, RYR1 stabilization may be a potential adjunctive therapeutic approach in DMD, the authors said.
DMD is characterized by progressive muscle damage, inadequate muscle regeneration due to impaired myogenesis and differentiation, and Ca2+ mishandling. RYR1 is the main mediator of Ca2+ release from the sarcoplasmic reticulum.
Here, a team of researchers led by Gilles Carnac, PhD, from the University of Montpellier in France investigated whether altered RYR1-mediated Ca2+ release may be contributing to the impairment of myogenic differentiation in patients with DMD.
Read more about DMD etiology
The researchers grew myoblasts in cultures obtained from 6 patients with DMD and 5 healthy controls. Their first observation was that the differentiation of myoblasts from patients with DMD was delayed compared to healthy controls.
Then, the researchers silenced the expression of the RYR1 gene in the healthy myoblasts and saw that this led to a delay as in the case of DMD myoblasts. When they measured the resting intracellular Ca2+ concentration in myotubes, they found that this concentration was increased in the case of DMD, but RYR1-mediated Ca2+ release remained unchanged.
The intracellular Ca2+ concentration correlated with endomysial fibrosis, the only myopathologic parameter affiliated with poor motor function in DMD.
The researchers also treated the DMD myotubes with S107, a molecule that stabilizes the interaction between RYR1 and calstabin, and saw that this led to a decrease in resting Ca2+ reaching control values and also improved myogenic differentiation.
“This suggested a potential relationship between RYR1 dysfunction and motor impairment,” the researchers said and proposed RYR1 stabilization as a therapeutic strategy in DMD.
Meyer P, Notarnicola C, Meli AC, et al. Skeletal ryanodine receptors are involved in impaired myogenic differentiation in Duchenne muscular dystrophy patients. Int J Mol Sci. 2021;30(23):12985. doi:10.3390/ijms222312985