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Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency

Crombie, DE, Curl, CL, Raaijmakers, AJ, Sivakumaran, P, Kulkarni, T, Wong, RCB, Minami, I, Evans-Galea, MV, Lim, SY, Delbridge, L, Corben, LA, Dottori, M, Nakatsuji, N, Trounce, IA, Hewitt, AW ORCID: 0000-0002-5123-5999, Delatycki, MB, Pera, MF and Pebay, A 2017 , 'Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency' , Aging, vol. 9, no. 5 , pp. 1440-1452 , doi:

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We sought to identify the impacts of Friedreich's ataxia (FRDA) on cardiomyocytes. FRDA is an autosomal recessive degenerative condition with neuronal and non-neuronal manifestations, the latter including progressive cardiomyopathy of the left ventricle, the leading cause of death in FRDA. Little is known about the cellular pathogenesis of FRDA in cardiomyocytes. Induced pluripotent stem cells (iPSCs) were derived from three FRDA individuals with characterized GAA repeats. The cells were differentiated into cardiomyocytes to assess phenotypes. FRDA iPSC- cardiomyocytes retained low levels of FRATAXIN (FXN) mRNA and protein. Electrophysiology revealed an increased variation of FRDA- cardiomyocyte beating rates which was prevented by addition of nifedipine, suggestive of a calcium handling deficiency. Finally, calcium imaging was performed and we identified small amplitude, diastolic and systolic calcium transients confirming a deficiency in calcium handling. We defined a robust FRDA cardiac-specific electrophysiological profile in patient-derived iPSCs which could be used for high throughput compound screening. This cell-specific signature will contribute to the identification and screening of novel treatments for this life-threatening disease.

Item Type: Article
Authors/Creators:Crombie, DE and Curl, CL and Raaijmakers, AJ and Sivakumaran, P and Kulkarni, T and Wong, RCB and Minami, I and Evans-Galea, MV and Lim, SY and Delbridge, L and Corben, LA and Dottori, M and Nakatsuji, N and Trounce, IA and Hewitt, AW and Delatycki, MB and Pera, MF and Pebay, A
Keywords: Friedreich’s ataxia, cardiomyopathy, induced pluripotent stem cells, modelling
Journal or Publication Title: Aging
Publisher: Impact Journals LLC
ISSN: 1945-4589
DOI / ID Number:
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Copyright: Crombie et al. Licensed under Creative Commons Attribution 3.0 Unported (CC BY 3.0)

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