Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy

Anne Cecile Huby, Uzmee Mendsaikhan, Ken Takagi, Ruben Martherus, Janaka Wansapura, Nan Gong, Hanna Osinska, Jeanne F. James, Kristen Kramer, Kazuyoshi Saito, Jeffrey Robbins, Zaza Khuchua, Jeffrey Towbin, Enkhsaikhan Purevjav

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

BACKGROUND: Familial restrictive cardiomyopathy (FRCM) has a poor prognosis due to diastolic dysfunction and restrictive physiology (RP). Myocardial stiffness, with or without fibrosis, underlie RP, but the mechanism(s) of restrictive remodeling is unclear. Myopalladin (MYPN) is a messenger molecule that links structural and gene regulatory molecules via translocation from the Z-disk and I-bands to the nucleus in cardiomyocytes. Expression of N-terminal MYPN peptide results in severe disruption of the sarcomere.

OBJECTIVES: The aim was to study a nonsense MYPN-Q529X mutation previously identified in the FRCM family in an animal model to explore the molecular and pathogenic mechanisms of FRCM.

METHODS: Functional (echocardiography, cardiac magnetic resonance [CMR] imaging, electrocardiography), morphohistological, gene expression, and molecular studies were performed in knock-in heterozygote (MypnWT/Q526X) and homozygote mice harboring the human MYPN-Q529X mutation.

RESULTS: Echocardiographic and CMR imaging signs of diastolic dysfunction with preserved systolic function were identified in 12-week-old MypnWT/Q526X mice. Histology revealed interstitial and perivascular fibrosis without overt hypertrophic remodeling. Truncated MypnQ526X protein was found to translocate to the nucleus. Levels of total and nuclear cardiac ankyrin repeat protein (Carp/Ankrd1) and phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Erk1/2), Erk1/2, Smad2, and Akt were reduced. Up-regulation was evident for muscle LIM protein (Mlp), desmin, and heart failure (natriuretic peptide A [Nppa], Nppb, and myosin heavy chain 6) and fibrosis (transforming growth factor beta 1, alpha-smooth muscle actin, osteopontin, and periostin) markers.

CONCLUSIONS: Heterozygote MypnWT/Q526X knock-in mice develop RCM due to persistence of mutant MypnQ526X protein in the nucleus. Down-regulation of Carp and up-regulation of Mlp and desmin appear to augment fibrotic restrictive remodeling, and reduced Erk1/2 levels blunt a hypertrophic response in MypnWT/Q526X hearts.

Original languageEnglish (US)
Pages (from-to)2765-2776
Number of pages12
JournalJournal of the American College of Cardiology
Volume64
Issue number25
DOIs
StatePublished - Dec 30 2014

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Restrictive Cardiomyopathy
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Fibrosis
Desmin
Carps
Heterozygote
Up-Regulation
Magnetic Resonance Imaging
Ankyrin Repeat
Natriuretic Peptides
Sarcomeres
Mutation
Proteins
Osteopontin
Myosin Heavy Chains
Homozygote
Mutant Proteins
Regulator Genes
Mitogen-Activated Protein Kinases

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy. / Huby, Anne Cecile; Mendsaikhan, Uzmee; Takagi, Ken; Martherus, Ruben; Wansapura, Janaka; Gong, Nan; Osinska, Hanna; James, Jeanne F.; Kramer, Kristen; Saito, Kazuyoshi; Robbins, Jeffrey; Khuchua, Zaza; Towbin, Jeffrey; Purevjav, Enkhsaikhan.

In: Journal of the American College of Cardiology, Vol. 64, No. 25, 30.12.2014, p. 2765-2776.

Research output: Contribution to journalArticle

Huby, AC, Mendsaikhan, U, Takagi, K, Martherus, R, Wansapura, J, Gong, N, Osinska, H, James, JF, Kramer, K, Saito, K, Robbins, J, Khuchua, Z, Towbin, J & Purevjav, E 2014, 'Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy', Journal of the American College of Cardiology, vol. 64, no. 25, pp. 2765-2776. https://doi.org/10.1016/j.jacc.2014.09.071
Huby, Anne Cecile ; Mendsaikhan, Uzmee ; Takagi, Ken ; Martherus, Ruben ; Wansapura, Janaka ; Gong, Nan ; Osinska, Hanna ; James, Jeanne F. ; Kramer, Kristen ; Saito, Kazuyoshi ; Robbins, Jeffrey ; Khuchua, Zaza ; Towbin, Jeffrey ; Purevjav, Enkhsaikhan. / Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy. In: Journal of the American College of Cardiology. 2014 ; Vol. 64, No. 25. pp. 2765-2776.
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title = "Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy",
abstract = "BACKGROUND: Familial restrictive cardiomyopathy (FRCM) has a poor prognosis due to diastolic dysfunction and restrictive physiology (RP). Myocardial stiffness, with or without fibrosis, underlie RP, but the mechanism(s) of restrictive remodeling is unclear. Myopalladin (MYPN) is a messenger molecule that links structural and gene regulatory molecules via translocation from the Z-disk and I-bands to the nucleus in cardiomyocytes. Expression of N-terminal MYPN peptide results in severe disruption of the sarcomere.OBJECTIVES: The aim was to study a nonsense MYPN-Q529X mutation previously identified in the FRCM family in an animal model to explore the molecular and pathogenic mechanisms of FRCM.METHODS: Functional (echocardiography, cardiac magnetic resonance [CMR] imaging, electrocardiography), morphohistological, gene expression, and molecular studies were performed in knock-in heterozygote (MypnWT/Q526X) and homozygote mice harboring the human MYPN-Q529X mutation.RESULTS: Echocardiographic and CMR imaging signs of diastolic dysfunction with preserved systolic function were identified in 12-week-old MypnWT/Q526X mice. Histology revealed interstitial and perivascular fibrosis without overt hypertrophic remodeling. Truncated MypnQ526X protein was found to translocate to the nucleus. Levels of total and nuclear cardiac ankyrin repeat protein (Carp/Ankrd1) and phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Erk1/2), Erk1/2, Smad2, and Akt were reduced. Up-regulation was evident for muscle LIM protein (Mlp), desmin, and heart failure (natriuretic peptide A [Nppa], Nppb, and myosin heavy chain 6) and fibrosis (transforming growth factor beta 1, alpha-smooth muscle actin, osteopontin, and periostin) markers.CONCLUSIONS: Heterozygote MypnWT/Q526X knock-in mice develop RCM due to persistence of mutant MypnQ526X protein in the nucleus. Down-regulation of Carp and up-regulation of Mlp and desmin appear to augment fibrotic restrictive remodeling, and reduced Erk1/2 levels blunt a hypertrophic response in MypnWT/Q526X hearts.",
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T1 - Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy

AU - Huby, Anne Cecile

AU - Mendsaikhan, Uzmee

AU - Takagi, Ken

AU - Martherus, Ruben

AU - Wansapura, Janaka

AU - Gong, Nan

AU - Osinska, Hanna

AU - James, Jeanne F.

AU - Kramer, Kristen

AU - Saito, Kazuyoshi

AU - Robbins, Jeffrey

AU - Khuchua, Zaza

AU - Towbin, Jeffrey

AU - Purevjav, Enkhsaikhan

PY - 2014/12/30

Y1 - 2014/12/30

N2 - BACKGROUND: Familial restrictive cardiomyopathy (FRCM) has a poor prognosis due to diastolic dysfunction and restrictive physiology (RP). Myocardial stiffness, with or without fibrosis, underlie RP, but the mechanism(s) of restrictive remodeling is unclear. Myopalladin (MYPN) is a messenger molecule that links structural and gene regulatory molecules via translocation from the Z-disk and I-bands to the nucleus in cardiomyocytes. Expression of N-terminal MYPN peptide results in severe disruption of the sarcomere.OBJECTIVES: The aim was to study a nonsense MYPN-Q529X mutation previously identified in the FRCM family in an animal model to explore the molecular and pathogenic mechanisms of FRCM.METHODS: Functional (echocardiography, cardiac magnetic resonance [CMR] imaging, electrocardiography), morphohistological, gene expression, and molecular studies were performed in knock-in heterozygote (MypnWT/Q526X) and homozygote mice harboring the human MYPN-Q529X mutation.RESULTS: Echocardiographic and CMR imaging signs of diastolic dysfunction with preserved systolic function were identified in 12-week-old MypnWT/Q526X mice. Histology revealed interstitial and perivascular fibrosis without overt hypertrophic remodeling. Truncated MypnQ526X protein was found to translocate to the nucleus. Levels of total and nuclear cardiac ankyrin repeat protein (Carp/Ankrd1) and phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Erk1/2), Erk1/2, Smad2, and Akt were reduced. Up-regulation was evident for muscle LIM protein (Mlp), desmin, and heart failure (natriuretic peptide A [Nppa], Nppb, and myosin heavy chain 6) and fibrosis (transforming growth factor beta 1, alpha-smooth muscle actin, osteopontin, and periostin) markers.CONCLUSIONS: Heterozygote MypnWT/Q526X knock-in mice develop RCM due to persistence of mutant MypnQ526X protein in the nucleus. Down-regulation of Carp and up-regulation of Mlp and desmin appear to augment fibrotic restrictive remodeling, and reduced Erk1/2 levels blunt a hypertrophic response in MypnWT/Q526X hearts.

AB - BACKGROUND: Familial restrictive cardiomyopathy (FRCM) has a poor prognosis due to diastolic dysfunction and restrictive physiology (RP). Myocardial stiffness, with or without fibrosis, underlie RP, but the mechanism(s) of restrictive remodeling is unclear. Myopalladin (MYPN) is a messenger molecule that links structural and gene regulatory molecules via translocation from the Z-disk and I-bands to the nucleus in cardiomyocytes. Expression of N-terminal MYPN peptide results in severe disruption of the sarcomere.OBJECTIVES: The aim was to study a nonsense MYPN-Q529X mutation previously identified in the FRCM family in an animal model to explore the molecular and pathogenic mechanisms of FRCM.METHODS: Functional (echocardiography, cardiac magnetic resonance [CMR] imaging, electrocardiography), morphohistological, gene expression, and molecular studies were performed in knock-in heterozygote (MypnWT/Q526X) and homozygote mice harboring the human MYPN-Q529X mutation.RESULTS: Echocardiographic and CMR imaging signs of diastolic dysfunction with preserved systolic function were identified in 12-week-old MypnWT/Q526X mice. Histology revealed interstitial and perivascular fibrosis without overt hypertrophic remodeling. Truncated MypnQ526X protein was found to translocate to the nucleus. Levels of total and nuclear cardiac ankyrin repeat protein (Carp/Ankrd1) and phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Erk1/2), Erk1/2, Smad2, and Akt were reduced. Up-regulation was evident for muscle LIM protein (Mlp), desmin, and heart failure (natriuretic peptide A [Nppa], Nppb, and myosin heavy chain 6) and fibrosis (transforming growth factor beta 1, alpha-smooth muscle actin, osteopontin, and periostin) markers.CONCLUSIONS: Heterozygote MypnWT/Q526X knock-in mice develop RCM due to persistence of mutant MypnQ526X protein in the nucleus. Down-regulation of Carp and up-regulation of Mlp and desmin appear to augment fibrotic restrictive remodeling, and reduced Erk1/2 levels blunt a hypertrophic response in MypnWT/Q526X hearts.

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