Characterisation of infantile cardiomyopathy in Alström syndrome using ALMS1 knockout induced pluripotent stem cell derived cardiomyocyte model.

Autor: Patel L; Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK. Electronic address: LXP062@student.bham.ac.uk., Roy A; Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK; Department of Cardiology, Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham, Birmingham, UK., Barlow J; Cellular Health and Metabolism Facility, School of Sport, Exercise and Rehabilitation, University of Birmingham, Birmingham, UK., O'Shea C; Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK., Nieves D; Institute of Immunology and Immunotherapy, University of Birmingham, UK., Azad AJ; Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK; Center of Biological Design, Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany., Hall C; Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK., Davies B; Genetic Modification Service, The Francis Crick Institute, London, UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK., Rath P; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK., Pavlovic D; Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK., Chikermane A; Paediatric Cardiology, Birmingham Children's Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham, Birmingham, UK., Geberhiwot T; Department of Inherited Metabolic Diseases, University Hospital Birmingham NHS Foundation Trust, Birmingham, Birmingham, UK; Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK., Steeds RP; Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK; Department of Cardiology, Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham, Birmingham, UK., Gehmlich K; Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK; Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford, UK. Electronic address: k.gehmlich@bham.ac.uk.
Jazyk: angličtina
Zdroj: Molecular genetics and metabolism [Mol Genet Metab] 2024 Sep-Oct; Vol. 143 (1-2), pp. 108575. Date of Electronic Publication: 2024 Sep 02.
DOI: 10.1016/j.ymgme.2024.108575
Abstrakt: Alström syndrome (AS) is an inherited rare ciliopathy characterised by multi-organ dysfunction and premature cardiovascular disease. This may manifest as an infantile-onset dilated cardiomyopathy with significant associated mortality. An adult-onset restrictive cardiomyopathy may also feature later in life. Loss of function pathogenic variants in ALMS1 have been identified in AS patients, leading to a lack of ALMS1 protein. The biological role of ALMS1 is unknown, particularly in a cardiovascular context. To understand the role of ALMS1 in infantile cardiomyopathy, the reduction of ALMS1 protein seen in AS patients was modelled using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), in which ALMS1 was knocked out. MuscleMotion analysis and calcium optical mapping experiments suggest that ALMS1 knockout (KO) cells have increased contractility, with altered calcium extrusion and impaired calcium handling dynamics compared to wildtype (WT) counterparts. Seahorse metabolic assays showed ALMS1 knockout iPSC-CMs had increased glycolytic and mitochondrial respiration rates, with ALMS1 knockout cells portraying increased energetic demand and respiratory capacity than WT counterparts. Using senescence associated β-galactosidase (SA-β gal) staining assay, we identified increased senescence of ALMS1 knockout iPSC-CMs. Overall, this study provides insights into the molecular mechanisms in AS, particularly the role of ALMS1 in infantile cardiomyopathy in AS, using iPSC-CMs as a 'disease in a dish' model to provide insights into multiple aspects of this complex disease.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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