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ACTN2 Mutant Causes Proteopathy in Human iPSC-Derived Cardiomyocytes

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ACTN2 Mutant Causes Proteopathy in Human iPSC-Derived Cardiomyocytes. / Zech, Antonia T L; Prondzynski, Maksymilian; Singh, Sonia R; Pietsch, Niels; Orthey, Ellen; Alizoti, Erda; Busch, Josefine; Madsen, Alexandra; Behrens, Charlotta S; Meyer-Jens, Moritz; Mearini, Giulia; Lemoine, Marc D; Krämer, Elisabeth; Mosqueira, Diogo; Virdi, Sanamjeet; Indenbirken, Daniela; Depke, Maren; Salazar, Manuela Gesell; Völker, Uwe; Braren, Ingke; Pu, William T; Eschenhagen, Thomas; Hammer, Elke; Schlossarek, Saskia; Carrier, Lucie.

In: CELLS-BASEL, Vol. 11, No. 17, 2745, 02.09.2022.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Zech, ATL, Prondzynski, M, Singh, SR, Pietsch, N, Orthey, E, Alizoti, E, Busch, J, Madsen, A, Behrens, CS, Meyer-Jens, M, Mearini, G, Lemoine, MD, Krämer, E, Mosqueira, D, Virdi, S, Indenbirken, D, Depke, M, Salazar, MG, Völker, U, Braren, I, Pu, WT, Eschenhagen, T, Hammer, E, Schlossarek, S & Carrier, L 2022, 'ACTN2 Mutant Causes Proteopathy in Human iPSC-Derived Cardiomyocytes', CELLS-BASEL, vol. 11, no. 17, 2745. https://doi.org/10.3390/cells11172745

APA

Zech, A. T. L., Prondzynski, M., Singh, S. R., Pietsch, N., Orthey, E., Alizoti, E., Busch, J., Madsen, A., Behrens, C. S., Meyer-Jens, M., Mearini, G., Lemoine, M. D., Krämer, E., Mosqueira, D., Virdi, S., Indenbirken, D., Depke, M., Salazar, M. G., Völker, U., ... Carrier, L. (2022). ACTN2 Mutant Causes Proteopathy in Human iPSC-Derived Cardiomyocytes. CELLS-BASEL, 11(17), [2745]. https://doi.org/10.3390/cells11172745

Vancouver

Zech ATL, Prondzynski M, Singh SR, Pietsch N, Orthey E, Alizoti E et al. ACTN2 Mutant Causes Proteopathy in Human iPSC-Derived Cardiomyocytes. CELLS-BASEL. 2022 Sep 2;11(17). 2745. https://doi.org/10.3390/cells11172745

Bibtex

@article{f158e3f08c9f4e1386ac0458029bf621,
title = "ACTN2 Mutant Causes Proteopathy in Human iPSC-Derived Cardiomyocytes",
abstract = "Genetic variants in α-actinin-2 (ACTN2) are associated with several forms of (cardio)myopathy. We previously reported a heterozygous missense (c.740C>T) ACTN2 gene variant, associated with hypertrophic cardiomyopathy, and characterized by an electro-mechanical phenotype in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Here, we created with CRISPR/Cas9 genetic tools two heterozygous functional knock-out hiPSC lines with a second wild-type (ACTN2wt) and missense ACTN2 (ACTN2mut) allele, respectively. We evaluated their impact on cardiomyocyte structure and function, using a combination of different technologies, including immunofluorescence and live cell imaging, RNA-seq, and mass spectrometry. This study showed that ACTN2mut presents a higher percentage of multinucleation, protein aggregation, hypertrophy, myofibrillar disarray, and activation of both the ubiquitin-proteasome system and the autophagy-lysosomal pathway as compared to ACTN2wt in 2D-cultured hiPSC-CMs. Furthermore, the expression of ACTN2mut was associated with a marked reduction of sarcomere-associated protein levels in 2D-cultured hiPSC-CMs and force impairment in engineered heart tissues. In conclusion, our study highlights the activation of proteolytic systems in ACTN2mut hiPSC-CMs likely to cope with ACTN2 aggregation and therefore directs towards proteopathy as an additional cellular pathology caused by this ACTN2 variant, which may contribute to human ACTN2-associated cardiomyopathies.",
keywords = "Actinin/genetics, Cardiomyopathy, Hypertrophic/metabolism, Humans, Induced Pluripotent Stem Cells/metabolism, Myocytes, Cardiac/metabolism, Sarcomeres/metabolism",
author = "Zech, {Antonia T L} and Maksymilian Prondzynski and Singh, {Sonia R} and Niels Pietsch and Ellen Orthey and Erda Alizoti and Josefine Busch and Alexandra Madsen and Behrens, {Charlotta S} and Moritz Meyer-Jens and Giulia Mearini and Lemoine, {Marc D} and Elisabeth Kr{\"a}mer and Diogo Mosqueira and Sanamjeet Virdi and Daniela Indenbirken and Maren Depke and Salazar, {Manuela Gesell} and Uwe V{\"o}lker and Ingke Braren and Pu, {William T} and Thomas Eschenhagen and Elke Hammer and Saskia Schlossarek and Lucie Carrier",
year = "2022",
month = sep,
day = "2",
doi = "10.3390/cells11172745",
language = "English",
volume = "11",
journal = "CELLS-BASEL",
issn = "2073-4409",
publisher = "MDPI Multidisciplinary Digital Publishing Institute",
number = "17",

}

RIS

TY - JOUR

T1 - ACTN2 Mutant Causes Proteopathy in Human iPSC-Derived Cardiomyocytes

AU - Zech, Antonia T L

AU - Prondzynski, Maksymilian

AU - Singh, Sonia R

AU - Pietsch, Niels

AU - Orthey, Ellen

AU - Alizoti, Erda

AU - Busch, Josefine

AU - Madsen, Alexandra

AU - Behrens, Charlotta S

AU - Meyer-Jens, Moritz

AU - Mearini, Giulia

AU - Lemoine, Marc D

AU - Krämer, Elisabeth

AU - Mosqueira, Diogo

AU - Virdi, Sanamjeet

AU - Indenbirken, Daniela

AU - Depke, Maren

AU - Salazar, Manuela Gesell

AU - Völker, Uwe

AU - Braren, Ingke

AU - Pu, William T

AU - Eschenhagen, Thomas

AU - Hammer, Elke

AU - Schlossarek, Saskia

AU - Carrier, Lucie

PY - 2022/9/2

Y1 - 2022/9/2

N2 - Genetic variants in α-actinin-2 (ACTN2) are associated with several forms of (cardio)myopathy. We previously reported a heterozygous missense (c.740C>T) ACTN2 gene variant, associated with hypertrophic cardiomyopathy, and characterized by an electro-mechanical phenotype in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Here, we created with CRISPR/Cas9 genetic tools two heterozygous functional knock-out hiPSC lines with a second wild-type (ACTN2wt) and missense ACTN2 (ACTN2mut) allele, respectively. We evaluated their impact on cardiomyocyte structure and function, using a combination of different technologies, including immunofluorescence and live cell imaging, RNA-seq, and mass spectrometry. This study showed that ACTN2mut presents a higher percentage of multinucleation, protein aggregation, hypertrophy, myofibrillar disarray, and activation of both the ubiquitin-proteasome system and the autophagy-lysosomal pathway as compared to ACTN2wt in 2D-cultured hiPSC-CMs. Furthermore, the expression of ACTN2mut was associated with a marked reduction of sarcomere-associated protein levels in 2D-cultured hiPSC-CMs and force impairment in engineered heart tissues. In conclusion, our study highlights the activation of proteolytic systems in ACTN2mut hiPSC-CMs likely to cope with ACTN2 aggregation and therefore directs towards proteopathy as an additional cellular pathology caused by this ACTN2 variant, which may contribute to human ACTN2-associated cardiomyopathies.

AB - Genetic variants in α-actinin-2 (ACTN2) are associated with several forms of (cardio)myopathy. We previously reported a heterozygous missense (c.740C>T) ACTN2 gene variant, associated with hypertrophic cardiomyopathy, and characterized by an electro-mechanical phenotype in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Here, we created with CRISPR/Cas9 genetic tools two heterozygous functional knock-out hiPSC lines with a second wild-type (ACTN2wt) and missense ACTN2 (ACTN2mut) allele, respectively. We evaluated their impact on cardiomyocyte structure and function, using a combination of different technologies, including immunofluorescence and live cell imaging, RNA-seq, and mass spectrometry. This study showed that ACTN2mut presents a higher percentage of multinucleation, protein aggregation, hypertrophy, myofibrillar disarray, and activation of both the ubiquitin-proteasome system and the autophagy-lysosomal pathway as compared to ACTN2wt in 2D-cultured hiPSC-CMs. Furthermore, the expression of ACTN2mut was associated with a marked reduction of sarcomere-associated protein levels in 2D-cultured hiPSC-CMs and force impairment in engineered heart tissues. In conclusion, our study highlights the activation of proteolytic systems in ACTN2mut hiPSC-CMs likely to cope with ACTN2 aggregation and therefore directs towards proteopathy as an additional cellular pathology caused by this ACTN2 variant, which may contribute to human ACTN2-associated cardiomyopathies.

KW - Actinin/genetics

KW - Cardiomyopathy, Hypertrophic/metabolism

KW - Humans

KW - Induced Pluripotent Stem Cells/metabolism

KW - Myocytes, Cardiac/metabolism

KW - Sarcomeres/metabolism

U2 - 10.3390/cells11172745

DO - 10.3390/cells11172745

M3 - SCORING: Journal article

C2 - 36078153

VL - 11

JO - CELLS-BASEL

JF - CELLS-BASEL

SN - 2073-4409

IS - 17

M1 - 2745

ER -