IPSC derived cardiac fibroblasts of DMD patients show compromised actin microfilaments, metabolic shift and pro-fibrotic phenotype

Biology Direct

Research

Josè-Manuel Pioner¹  Andrea Gottinger²  Jason S. Iacovoni³  Olivier Lairez⁴  Angelo Parini⁴  Nathalie Pizzinat⁴  Lesia Savchenko⁴  Salwa Soussi⁴  Andrea Farini⁵  Aoife Gowran⁶  Sara Mallia⁶  Davide Rovina⁶  Martina Rabino⁶  Giulio Pompilio⁷  Maxime Vialettes⁸ 

[1] Department of Biology, University of Florence, Florence, Italy;National Institute of Health and Medical Research (INSERM), I2MC, U1297, Toulouse, France;National Institute of Health and Medical Research (INSERM), I2MC, U1297, Toulouse, France;National Institute of Health and Medical Research (INSERM) U1297 I2MC, Bioinformatic Core Facility, I2MC, Toulouse, France;National Institute of Health and Medical Research (INSERM), I2MC, U1297, Toulouse, France;University Toulouse III, 118 route de Narbonne, 31062 Toulouse, CEDEX 9, Toulouse, France;Neurology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy;Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, Milan, Italy;Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, Milan, Italy;Department of Biomedical, Surgical and Dental Sciences, Università Degli Studi di Milano, Milan, Italy;University Toulouse III, 118 route de Narbonne, 31062 Toulouse, CEDEX 9, Toulouse, France;

关键词: Duchenne;    Human induced pluripotent stem cell;    Fibroblasts;    Mitochondrial oxidation;    Actin microfilaments;   

DOI  :  10.1186/s13062-023-00398-2

 received in 2023-06-29, accepted in 2023-07-21,  发布年份 2023

来源: Springer

【 摘 要 】

Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy caused by mutations in the dystrophin gene. We characterized which isoforms of dystrophin were expressed by human induced pluripotent stem cell (hiPSC)-derived cardiac fibroblasts obtained from control and DMD patients. Distinct dystrophin isoforms were observed; however, highest molecular weight isoform was absent in DMD patients carrying exon deletions or mutations in the dystrophin gene. The loss of the full-length dystrophin isoform in hiPSC-derived cardiac fibroblasts from DMD patients resulted in deficient formation of actin microfilaments and a metabolic switch from mitochondrial oxidation to glycolysis. The DMD hiPSC-derived cardiac fibroblasts exhibited a dysregulated mitochondria network and reduced mitochondrial respiration, with enhanced compensatory glycolysis to sustain cellular ATP production. This metabolic remodeling was associated with an exacerbated myofibroblast phenotype and increased fibroblast activation in response to pro fibrotic challenges. As cardiac fibrosis is a critical pathological feature of the DMD heart, the myofibroblast phenotype induced by the absence of dystrophin may contribute to deterioration in cardiac function. Our study highlights the relationship between cytoskeletal dynamics, metabolism of the cell and myofibroblast differentiation and provides a new mechanism by which inactivation of dystrophin in non-cardiomyocyte cells may increase the severity of cardiopathy.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023. corrected publication 2023

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