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Bioenergetic and Metabolic Impairments in Induced Pluripotent Stem Cell-Derived Cardiomyocytes Generated from Duchenne Muscular Dystrophy Patients.

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.

SUBMITTER: Willi L

PROVIDER: S-EPMC9456153 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Bioenergetic and Metabolic Impairments in Induced Pluripotent Stem Cell-Derived Cardiomyocytes Generated from Duchenne Muscular Dystrophy Patients.

Willi Lubna L Abramovich Ifat I Fernandez-Garcia Jonatan J Agranovich Bella B Shulman Margarita M Milman Helena H Baskin Polina P Eisen Binyamin B Michele Daniel E DE Arad Michael M Binah Ofer O Gottlieb Eyal E

International journal of molecular sciences 20220829 17

Duchenne muscular dystrophy (DMD) is caused by mutations in the <i>dystrophin</i> 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 hy ...[more]

PMID: 36077200

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Project description:BackgroundAlthough cardiomyopathy has emerged as a leading cause of death in Duchenne muscular dystrophy (DMD), limited studies and therapies have emerged for dystrophic heart failure.ObjectivesThe purpose of this study was to model DMD cardiomyopathy using DMD patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and to identify physiological changes and future drug therapies.MethodsTo explore and define therapies for DMD cardiomyopathy, the authors used DMD patient-specific hiPSC-derived cardiomyocytes to examine the physiological response to adrenergic agonists and β-blocker treatment. The authors further examined these agents in vivo using wild-type and mdx mouse models.ResultsAt baseline and following adrenergic stimulation, DMD hiPSC-derived cardiomyocytes had a significant increase in arrhythmic calcium traces compared to isogenic controls. Furthermore, these arrhythmias were significantly decreased with propranolol treatment. Using telemetry monitoring, the authors observed that mdx mice, which lack dystrophin, had an arrhythmic death when stimulated with isoproterenol; the lethal arrhythmias were rescued, in part, by propranolol pre-treatment. Using single-cell and bulk RNA sequencing (RNA-seq), the authors compared DMD and control hiPSC-derived cardiomyocytes, mdx mice, and control mice (in the presence or absence of propranolol and isoproterenol) and defined pathways that were perturbed under baseline conditions and pathways that were normalized after propranolol treatment in the mdx model. The authors also undertook transcriptome analysis of human DMD left ventricle samples and found that DMD hiPSC-derived cardiomyocytes have dysregulated pathways similar to the human DMD heart. The authors further determined that relatively few patients with DMD see a cardiovascular specialist or receive β-blocker therapy.ConclusionsThe results highlight mechanisms and therapeutic interventions from human to animal and back to human in the dystrophic heart. These results may serve as a prelude for an adequately powered clinical study that examines the impact of β-blocker therapy in patients with dystrophinopathies.

Project description:BackgroundInsights into the progression of muscle impairments in growing boys with Duchenne muscular dystrophy (DMD) remain incomplete due to the frequent oversight of normal maturation as a confounding factor, thereby restricting the delineation of sole pathological processes.ObjectiveTo establish longitudinal trajectories for a comprehensive integrated set of muscle impairments, including muscle weakness, contractures and muscle size alterations, while correcting for normal maturation, in DMD.MethodsThirty-three boys with DMD (aged 4.3-17 years) were included. Fixed dynamometry, goniometry, and 3D freehand ultrasound were used to repeatedly assess lower limb muscle strength, passive range of motion (ROM) and muscle size, resulting in 161, 178 and 64 assessments for the strength, ROM and ultrasound dataset, respectively. To account for natural strength development, ROM reduction, and muscle growth in growing children, muscle outcomes were converted to unit-less z-scores calculated in reference to typically developing (TD) peers. This allows the interpretation of the muscle outcomes as deficits or alterations with respect to TD. Mixed-effect models estimated the longitudinal change in muscle impairments.ResultsAt 4.3-4.9 years of age, all muscle strength outcomes and several ROMs (i.e., dorsiflexion, hamstrings, and hip extension) showed deficits relative to TD, while m. medial gastrocnemius size was increased. Most muscle outcomes remained stable or slightly improved until the ages of 6.6-9.4 years (except knee flexion strength). After this period, muscle strength (-0.27 to -0.45 z-score/year; p < 0.0044), dorsiflexion ROM (-0.23 to -0.33 z-score/year; p < 0.0007), m. medial gastrocnemius size (-0.56 z-score/year; p = 0.0022), and m. rectus femoris size (-0.36 z-score/year; p = 0.0054) declined.ConclusionsThe current study established longitudinal trajectories of muscle impairments in boys with DMD. The results provided enriched history data and revealed promising outcome measures that could enhance the detection of the efficacy of novel therapeutic strategies. Future studies are necessary to validate these outcomes.

Dataset Information

Bioenergetic and Metabolic Impairments in Induced Pluripotent Stem Cell-Derived Cardiomyocytes Generated from Duchenne Muscular Dystrophy Patients.

Publications

Bioenergetic and Metabolic Impairments in Induced Pluripotent Stem Cell-Derived Cardiomyocytes Generated from Duchenne Muscular Dystrophy Patients.

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