Bioenergetic and Metabolic Impairments in Induced Pluripotent Stem Cell-Derived Cardiomyocytes Generated from Duchenne Muscular Dystrophy Patients
Summary
Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene and dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality in DMD patients. We tested the hypothesis that DCM is caused by metabolic impairments by employing induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from four DMD patients; an adult male, an adult female, a 7-year-old (7y) male and a 13-year-old (13y) male, all compared to two healthy volunteers. To test the hypothesis, we measured the bioenergetics, metabolomics, electrophysiology, mitochondrial morphology and mitochondrial activity of CMs, using respirometry, LC-MS, patch clamp, electron microscopy (EM) and confocal microscopy methods. We found that: (1) adult DMD CMs exhibited impaired energy metabolism and abnormal mitochondrial structure and function. (2) The 7y CMs demonstrated arrhythmia-free spontaneous firing along with "healthy-like" metabolic status, normal mitochondrial morphology and activity. In contrast, the 13y CMs were mildly arrhythmogenic and showed adult DMD-like bioenergetics deficiencies. (3) In DMD adult CMs, mitochondrial activities were attenuated by 45-48%, whereas the 7y CM activity was similar to that of healthy CMs. (4) In DMD CMs, but not in 7y CMs, there was a 75% decrease in the mitochondrial ATP production rate compared to healthy iPSC-CMs. In summary, DMD iPSC-CMs exhibit bioenergetic and metabolic impairments that are associated with rhythm disturbances corresponding to the patient's phenotype, thereby constituting novel targets for alleviating cardiomyopathy in DMD patients.
| Authors | Willi L, Abramovich I, Fernandez-Garcia J, Agranovich B, Shulman M, Milman H, Baskin P, Eisen B, Michele DE, Arad M, Binah O, Gottlieb E |
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| Journal | International journal of molecular sciences |
| Publication Date | 2022 Aug 29;23(17) |
| PubMed | 36077200 |
| PubMed Central | PMC9456153 |
| DOI | 10.3390/ijms23179808 |