Research Article: The intracellular Ca2+ concentration is elevated in cardiomyocytes differentiated from hiPSCs derived from a Duchenne muscular dystrophy patient

Date Published: March 15, 2019

Publisher: Public Library of Science

Author(s): Fumitoshi Tsurumi, Shiro Baba, Daisuke Yoshinaga, Katsutsugu Umeda, Takuya Hirata, Junko Takita, Toshio Heike, Atsushi Asakura.


Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy. The major symptoms of this condition are walking difficulties, dyspnea caused by progressive skeletal muscle weakness, and cardiomyopathy. Recent advances in ventilator support devices have dramatically decreased mortality caused by respiratory distress. Consequently, cardiomyopathy resulting in heart failure is currently the major cause of death among DMD patients. One mechanism by which skeletal muscle is damaged in DMD patients involves elevation of the intracellular Ca2+ concentration. By contrast, the mechanisms underlying the development of cardiomyopathy are unclear. To investigate this, we examined the intracellular Ca2+ concentration and calcium transients in cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs). hiPSCs were derived from a DMD patient (DMD-hiPSCs), in whom exon 44 of the gene encoding dystrophin was deleted, and from his parents (control-hiPSCs), who did not carry this mutation. The intracellular Ca2+ concentration was measured using the fluorescent indicator indo-1. The fluorescence ratio (410/490 nm) of indo-1 at rest (R0), the peak of this ratio (Rmax), and the amplitude (Rmax—R0) were significantly higher in cardiomyocytes differentiated from DMD-hiPSCs than in those differentiated from control-hiPSCs. Moreover, mechanical stretching significantly increased the intracellular Ca2+ concentration in cardiomyocytes differentiated from DMD-hiPSCs, but not in those differentiated from control-hiPSCs. These findings indicate that elevation of the intracellular Ca2+ concentration can cause cardiac damage leading to cardiomyopathy in DMD patients.

Partial Text

Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy. This condition is caused by mutations of the gene encoding dystrophin located on chromosome Xp21 and is inherited in an autosomal recessive manner. DMD is relatively common, with an incidence of approximately 1 per 3500 male births. Muscle atrophy and weakness develop progressively with repeated cycles of muscle degeneration and regeneration. The majority of patients begin to experience walking difficulties before puberty. Patients usually develop respiratory muscle failure and heart failure, which are both common lethal complications of DMD, in their late teens and early twenties [1].

DMD is the most common and severe form of muscular dystrophy. Patients with this condition lack dystrophin, a major structural protein in muscle cells. Muscular atrophy resulting in muscle weakness develops progressively. DMD can also lead to DCM. Recent reports revealed that the percentage of DMD patients who die due to cardiac problems has rapidly increased, while the percentage who die due to respiratory complications has concomitantly decreased.

Calcium overload might be one mechanism by which cardiomyopathy develops in DMD patients. Reducing calcium overload is a potential strategy to treat cardiomyopathy in such patients.




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