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

Journal Article


Abstract


  • 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.

Authors


  •   Crombie, Duncan E. (external author)
  •   Curl, Claire L. (external author)
  •   Raaijmakers, Antonia J.A. (external author)
  •   Sivakumaran, Priyadharshini (external author)
  •   Kulkarni, Tejal (external author)
  •   Wong, Raymond (external author)
  •   Minami, Itsunari (external author)
  •   Evans-Galea, Marguerite V. (external author)
  •   Lim, Shiang Y. (external author)
  •   Delbridge, Lea M. D. (external author)
  •   Corben, Louise (external author)
  •   Dottori, Mirella
  •   Nakatsuji, Norio (external author)
  •   Trounce, Ian A. (external author)
  •   Hewitt, Alex W. (external author)
  •   Delatycki, Martin B. (external author)
  •   Pera, Martin F. (external author)
  •   Pebay, Alice (external author)

Publication Date


  • 2017

Published In


Citation


  • Crombie, D. E., Curl, C. L., Raaijmakers, A. J. A., Sivakumaran, P., Kulkarni, T., Wong, R. C. B., Minami, I., Evans-Galea, M. V., Lim, S. Y., Delbridge, L., Corben, L. A., Dottori, M., Nakatsuji, N., Trounce, I. A., Hewitt, A. W., Delatycki, M. B., Pera, M. F. & Pebay, A. (2017). Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency. Aging, 9 (5), 1440-1452.

Scopus Eid


  • 2-s2.0-85020125582

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1152

Has Global Citation Frequency


Number Of Pages


  • 12

Start Page


  • 1440

End Page


  • 1452

Volume


  • 9

Issue


  • 5

Place Of Publication


  • United States

Abstract


  • 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.

Authors


  •   Crombie, Duncan E. (external author)
  •   Curl, Claire L. (external author)
  •   Raaijmakers, Antonia J.A. (external author)
  •   Sivakumaran, Priyadharshini (external author)
  •   Kulkarni, Tejal (external author)
  •   Wong, Raymond (external author)
  •   Minami, Itsunari (external author)
  •   Evans-Galea, Marguerite V. (external author)
  •   Lim, Shiang Y. (external author)
  •   Delbridge, Lea M. D. (external author)
  •   Corben, Louise (external author)
  •   Dottori, Mirella
  •   Nakatsuji, Norio (external author)
  •   Trounce, Ian A. (external author)
  •   Hewitt, Alex W. (external author)
  •   Delatycki, Martin B. (external author)
  •   Pera, Martin F. (external author)
  •   Pebay, Alice (external author)

Publication Date


  • 2017

Published In


Citation


  • Crombie, D. E., Curl, C. L., Raaijmakers, A. J. A., Sivakumaran, P., Kulkarni, T., Wong, R. C. B., Minami, I., Evans-Galea, M. V., Lim, S. Y., Delbridge, L., Corben, L. A., Dottori, M., Nakatsuji, N., Trounce, I. A., Hewitt, A. W., Delatycki, M. B., Pera, M. F. & Pebay, A. (2017). Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency. Aging, 9 (5), 1440-1452.

Scopus Eid


  • 2-s2.0-85020125582

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1152

Has Global Citation Frequency


Number Of Pages


  • 12

Start Page


  • 1440

End Page


  • 1452

Volume


  • 9

Issue


  • 5

Place Of Publication


  • United States