Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload

Maria Carmela Filomena; Daniel L. Yamamoto; Pierluigi Carullo; Roman Medvedev; Andrea Ghisleni; Nicoletta Piroddi; Beatrice Scellini; Roberta Crispino; Francesca D’autilia; Jianlin Zhang; Arianna Felicetta; Simona Nemska; Simone Serio; Chiara Tesi; Daniele Catalucci; Wolfgang A. Linke; Roman Polishchuk; Corrado Poggesi; Mathias Gautel; Marie Louise Bang

doi:10.7554/eLife.58313

Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload

Maria Carmela Filomena, Daniel L. Yamamoto, Pierluigi Carullo, Roman Medvedev, Andrea Ghisleni, Nicoletta Piroddi, Beatrice Scellini, Roberta Crispino, Francesca D’autilia, Jianlin Zhang, Arianna Felicetta, Simona Nemska, Simone Serio, Chiara Tesi, Daniele Catalucci, Wolfgang A. Linke, Roman Polishchuk, Corrado Poggesi, Mathias Gautel, Marie Louise Bang^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

Abstract

Myopalladin (MYPN) is a striated muscle-specific immunoglobulin domain-containing protein located in the sarcomeric Z-line and I-band. MYPN gene mutations are causative for dilated (DCM), hypertrophic and restrictive cardiomyopathy. In a yeast two-hybrid screening, MYPN was found to bind to titin in the Z-line, which was confirmed by microscale thermophoresis. Cardiac analyses of MYPN knockout (MKO) mice showed the development of mild cardiac dilation and systolic dysfunction, associated with decreased myofibrillar isometric tension generation and increased resting tension at longer sarcomere lengths. MKO mice exhibited a normal hypertrophic response to transaortic constriction (TAC), but rapidly developed severe cardiac dilation and systolic dysfunction, associated with fibrosis, increased fetal gene expression, higher intercalated disc fold amplitude, decreased calsequestrin-2 protein levels, and increased desmoplakin and SORBS2 protein levels. Cardiomyocyte analyses showed delayed Ca²⁺ release and reuptake in unstressed MKO mice as well as reduced Ca²⁺ spark amplitude post-TAC, suggesting that altered Ca²⁺ handling may contribute to the development of DCM in MKO mice.

Original language	English
Article number	e58313
Journal	eLife
Volume	10
Early online date	24 Sept 2021
DOIs	https://doi.org/10.7554/eLife.58313
Publication status	Published - Sept 2021

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10.7554/eLife.58313

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Filomena, M. C., Yamamoto, D. L., Carullo, P., Medvedev, R., Ghisleni, A., Piroddi, N., Scellini, B., Crispino, R., D’autilia, F., Zhang, J., Felicetta, A., Nemska, S., Serio, S., Tesi, C., Catalucci, D., Linke, W. A., Polishchuk, R., Poggesi, C., Gautel, M., & Bang, M. L. (2021). Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload. eLife, 10, Article e58313. https://doi.org/10.7554/eLife.58313

@article{47a62b50342849ab906b1a2d103279a0,

title = "Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload",

abstract = "Myopalladin (MYPN) is a striated muscle-specific immunoglobulin domain-containing protein located in the sarcomeric Z-line and I-band. MYPN gene mutations are causative for dilated (DCM), hypertrophic and restrictive cardiomyopathy. In a yeast two-hybrid screening, MYPN was found to bind to titin in the Z-line, which was confirmed by microscale thermophoresis. Cardiac analyses of MYPN knockout (MKO) mice showed the development of mild cardiac dilation and systolic dysfunction, associated with decreased myofibrillar isometric tension generation and increased resting tension at longer sarcomere lengths. MKO mice exhibited a normal hypertrophic response to transaortic constriction (TAC), but rapidly developed severe cardiac dilation and systolic dysfunction, associated with fibrosis, increased fetal gene expression, higher intercalated disc fold amplitude, decreased calsequestrin-2 protein levels, and increased desmoplakin and SORBS2 protein levels. Cardiomyocyte analyses showed delayed Ca2+ release and reuptake in unstressed MKO mice as well as reduced Ca2+ spark amplitude post-TAC, suggesting that altered Ca2+ handling may contribute to the development of DCM in MKO mice.",

author = "Filomena, {Maria Carmela} and Yamamoto, {Daniel L.} and Pierluigi Carullo and Roman Medvedev and Andrea Ghisleni and Nicoletta Piroddi and Beatrice Scellini and Roberta Crispino and Francesca D{\textquoteright}autilia and Jianlin Zhang and Arianna Felicetta and Simona Nemska and Simone Serio and Chiara Tesi and Daniele Catalucci and Linke, {Wolfgang A.} and Roman Polishchuk and Corrado Poggesi and Mathias Gautel and Bang, {Marie Louise}",

note = "Funding Information: This work was supported by the Italian Telethon foundation [GGP12282 to Funding Information: This work was supported by the Italian Telethon foundation [GGP12282 to M.L.B.]; the Italian Space Agency [2015-009-R.0 to M.L.B.]; the Italian Ministry of Education, Universities and Research [MiUR PRIN 2010?2011; 2010R8JK2X_006 to M.L.B.]; the Italian Ministry of Health [RF-MUL-2007-666195 to M.L.B.]; the Cariplo foundation [2007.5812 to M.L.B.]; and the European Union?s Horizon 2020 research and innovation program [SILICOFCM; 777204 to C.P.]. A.G. was supported by the Wellcome Trust Collaborative Award in Science [201543/Z/16 to M.G.]. M.G. holds the British Heart Foundation Chair of Molecular Cardiology. Funding Information: The essential role of MYPN for normal cardiac function is supported by the identification of an Publisher Copyright: {\textcopyright} 2021, eLife Sciences Publications Ltd. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = sep,

doi = "10.7554/eLife.58313",

language = "English",

volume = "10",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications, Ltd",

}

Filomena, MC, Yamamoto, DL, Carullo, P, Medvedev, R, Ghisleni, A, Piroddi, N, Scellini, B, Crispino, R, D’autilia, F, Zhang, J, Felicetta, A, Nemska, S, Serio, S, Tesi, C, Catalucci, D, Linke, WA, Polishchuk, R, Poggesi, C, Gautel, M & Bang, ML 2021, 'Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload', eLife, vol. 10, e58313. https://doi.org/10.7554/eLife.58313

TY - JOUR

T1 - Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload

AU - Filomena, Maria Carmela

AU - Yamamoto, Daniel L.

AU - Carullo, Pierluigi

AU - Medvedev, Roman

AU - Ghisleni, Andrea

AU - Piroddi, Nicoletta

AU - Scellini, Beatrice

AU - Crispino, Roberta

AU - D’autilia, Francesca

AU - Zhang, Jianlin

AU - Felicetta, Arianna

AU - Nemska, Simona

AU - Serio, Simone

AU - Tesi, Chiara

AU - Catalucci, Daniele

AU - Linke, Wolfgang A.

AU - Polishchuk, Roman

AU - Poggesi, Corrado

AU - Gautel, Mathias

AU - Bang, Marie Louise

N1 - Funding Information: This work was supported by the Italian Telethon foundation [GGP12282 to Funding Information: This work was supported by the Italian Telethon foundation [GGP12282 to M.L.B.]; the Italian Space Agency [2015-009-R.0 to M.L.B.]; the Italian Ministry of Education, Universities and Research [MiUR PRIN 2010?2011; 2010R8JK2X_006 to M.L.B.]; the Italian Ministry of Health [RF-MUL-2007-666195 to M.L.B.]; the Cariplo foundation [2007.5812 to M.L.B.]; and the European Union?s Horizon 2020 research and innovation program [SILICOFCM; 777204 to C.P.]. A.G. was supported by the Wellcome Trust Collaborative Award in Science [201543/Z/16 to M.G.]. M.G. holds the British Heart Foundation Chair of Molecular Cardiology. Funding Information: The essential role of MYPN for normal cardiac function is supported by the identification of an Publisher Copyright: © 2021, eLife Sciences Publications Ltd. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/9

Y1 - 2021/9

N2 - Myopalladin (MYPN) is a striated muscle-specific immunoglobulin domain-containing protein located in the sarcomeric Z-line and I-band. MYPN gene mutations are causative for dilated (DCM), hypertrophic and restrictive cardiomyopathy. In a yeast two-hybrid screening, MYPN was found to bind to titin in the Z-line, which was confirmed by microscale thermophoresis. Cardiac analyses of MYPN knockout (MKO) mice showed the development of mild cardiac dilation and systolic dysfunction, associated with decreased myofibrillar isometric tension generation and increased resting tension at longer sarcomere lengths. MKO mice exhibited a normal hypertrophic response to transaortic constriction (TAC), but rapidly developed severe cardiac dilation and systolic dysfunction, associated with fibrosis, increased fetal gene expression, higher intercalated disc fold amplitude, decreased calsequestrin-2 protein levels, and increased desmoplakin and SORBS2 protein levels. Cardiomyocyte analyses showed delayed Ca2+ release and reuptake in unstressed MKO mice as well as reduced Ca2+ spark amplitude post-TAC, suggesting that altered Ca2+ handling may contribute to the development of DCM in MKO mice.

AB - Myopalladin (MYPN) is a striated muscle-specific immunoglobulin domain-containing protein located in the sarcomeric Z-line and I-band. MYPN gene mutations are causative for dilated (DCM), hypertrophic and restrictive cardiomyopathy. In a yeast two-hybrid screening, MYPN was found to bind to titin in the Z-line, which was confirmed by microscale thermophoresis. Cardiac analyses of MYPN knockout (MKO) mice showed the development of mild cardiac dilation and systolic dysfunction, associated with decreased myofibrillar isometric tension generation and increased resting tension at longer sarcomere lengths. MKO mice exhibited a normal hypertrophic response to transaortic constriction (TAC), but rapidly developed severe cardiac dilation and systolic dysfunction, associated with fibrosis, increased fetal gene expression, higher intercalated disc fold amplitude, decreased calsequestrin-2 protein levels, and increased desmoplakin and SORBS2 protein levels. Cardiomyocyte analyses showed delayed Ca2+ release and reuptake in unstressed MKO mice as well as reduced Ca2+ spark amplitude post-TAC, suggesting that altered Ca2+ handling may contribute to the development of DCM in MKO mice.

UR - http://www.scopus.com/inward/record.url?scp=85116335438&partnerID=8YFLogxK

U2 - 10.7554/eLife.58313

DO - 10.7554/eLife.58313

M3 - Article

AN - SCOPUS:85116335438

SN - 2050-084X

VL - 10

JO - eLife

JF - eLife

M1 - e58313

ER -

Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload

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