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Bioenergetic and Metabolic Impairments in Induced Pluripotent Stem Cell-Derived Cardiomyocytes Generated from
Lubna Willi1, Ifat Abramovich2, Jonatan Fernandez-Garcia2
1Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 31096, Israel.
Insights
Duchenne muscular dystrophy (DMD) patients develop cardiomyopathy due to metabolic issues. Stem cell-derived heart cells from DMD patients show impaired energy production and abnormal mitochondria, correlating with disease severity.
Area of Science:
- Cardiology
- Genetics
- Cell Biology
Background:
- Duchenne muscular dystrophy (DMD) is a genetic disorder caused by dystrophin gene mutations.
- Dilated cardiomyopathy (DCM) is a significant complication leading to morbidity and mortality in DMD patients.
- Metabolic impairments are hypothesized to underlie DCM development in DMD.
Purpose of the Study:
- To investigate the role of metabolic impairments in DCM development in DMD.
- To analyze bioenergetics, metabolomics, and mitochondrial function in DMD patient-derived cardiomyocytes (iPSC-CMs).
Main Methods:
- Generated iPSC-CMs from four DMD patients (adult male, adult female, 7-year-old male, 13-year-old male) and two healthy volunteers.
- Assessed cellular bioenergetics, metabolomics, electrophysiology, mitochondrial morphology, and activity.
- Utilized techniques including respirometry, LC-MS, patch clamp, electron microscopy, and confocal microscopy.
Main Results:
- Adult DMD iPSC-CMs displayed impaired energy metabolism, abnormal mitochondrial structure, and reduced mitochondrial activity (45-48% decrease).
- Younger (7-year-old) DMD iPSC-CMs showed healthy-like metabolism and mitochondrial function, with no arrhythmias.
- Older (13-year-old) DMD iPSC-CMs exhibited mild arrhythmogenicity and bioenergetic deficiencies similar to adult DMD iPSC-CMs.
- DMD iPSC-CMs showed a 75% decrease in mitochondrial ATP production rate compared to healthy controls.
Conclusions:
- DMD iPSC-CMs demonstrate significant bioenergetic and metabolic deficits.
- These impairments correlate with observed rhythm disturbances and patient phenotype.
- Metabolic dysfunction in cardiomyocytes represents a potential therapeutic target for DMD-associated cardiomyopathy.
Abstract:
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.
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