Activation of Autophagy Ameliorates Cardiomyopathy in Mybpc3-Targeted Knockin Mice

Sonia R. Singh, Antonia T.L. Zech, Birgit Geertz, Silke Reischmann-Düsener, Hanna Osinska, Maksymilian Prondzynski, Elisabeth Krämer, Qinghang Meng, Charles Redwood, Jolanda van der Velden, Jeffrey Robbins, Saskia Schlossarek, Lucie Carrier

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: Alterations in autophagy have been reported in hypertrophic cardiomyopathy (HCM) caused by Danon disease, Vici syndrome, or LEOPARD syndrome, but not in HCM caused by mutations in genes encoding sarcomeric proteins, which account for most of HCM cases. MYBPC3, encoding cMyBP-C (cardiac myosin-binding protein C), is the most frequently mutated HCM gene.

METHODS AND RESULTS: We evaluated autophagy in patients with HCM carrying MYBPC3 mutations and in a Mybpc3-targeted knockin HCM mouse model, as well as the effect of autophagy modulators on the development of cardiomyopathy in knockin mice. Microtubule-associated protein 1 light chain 3 (LC3)-II protein levels were higher in HCM septal myectomies than in nonfailing control hearts and in 60-week-old knockin than in wild-type mouse hearts. In contrast to wild-type, autophagic flux was blunted and associated with accumulation of residual bodies and glycogen in hearts of 60-week-old knockin mice. We found that Akt-mTORC1 (mammalian target of rapamycin complex 1) signaling was increased, and treatment with 2.24 mg/kg·d rapamycin or 40% caloric restriction for 9 weeks partially rescued cardiomyopathy or heart failure and restored autophagic flux in knockin mice.

CONCLUSIONS: Altogether, we found that (1) autophagy is altered in patients with HCM carrying MYBPC3 mutations, (2) autophagy is impaired in Mybpc3-targeted knockin mice, and (3) activation of autophagy ameliorated the cardiac disease phenotype in this mouse model. We propose that activation of autophagy might be an attractive option alone or in combination with another therapy to rescue HCM caused by MYBPC3 mutations.

Original languageEnglish
Article numbere004140
JournalCirculation. Heart failure
Volume10
Issue number10
DOIs
Publication statusPublished - 1 Oct 2017

Cite this

Singh, S. R., Zech, A. T. L., Geertz, B., Reischmann-Düsener, S., Osinska, H., Prondzynski, M., ... Carrier, L. (2017). Activation of Autophagy Ameliorates Cardiomyopathy in Mybpc3-Targeted Knockin Mice. Circulation. Heart failure, 10(10), [e004140]. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004140
Singh, Sonia R. ; Zech, Antonia T.L. ; Geertz, Birgit ; Reischmann-Düsener, Silke ; Osinska, Hanna ; Prondzynski, Maksymilian ; Krämer, Elisabeth ; Meng, Qinghang ; Redwood, Charles ; van der Velden, Jolanda ; Robbins, Jeffrey ; Schlossarek, Saskia ; Carrier, Lucie. / Activation of Autophagy Ameliorates Cardiomyopathy in Mybpc3-Targeted Knockin Mice. In: Circulation. Heart failure. 2017 ; Vol. 10, No. 10.
@article{5ea1070082034d4f9537b5e1e96803c8,
title = "Activation of Autophagy Ameliorates Cardiomyopathy in Mybpc3-Targeted Knockin Mice",
abstract = "BACKGROUND: Alterations in autophagy have been reported in hypertrophic cardiomyopathy (HCM) caused by Danon disease, Vici syndrome, or LEOPARD syndrome, but not in HCM caused by mutations in genes encoding sarcomeric proteins, which account for most of HCM cases. MYBPC3, encoding cMyBP-C (cardiac myosin-binding protein C), is the most frequently mutated HCM gene.METHODS AND RESULTS: We evaluated autophagy in patients with HCM carrying MYBPC3 mutations and in a Mybpc3-targeted knockin HCM mouse model, as well as the effect of autophagy modulators on the development of cardiomyopathy in knockin mice. Microtubule-associated protein 1 light chain 3 (LC3)-II protein levels were higher in HCM septal myectomies than in nonfailing control hearts and in 60-week-old knockin than in wild-type mouse hearts. In contrast to wild-type, autophagic flux was blunted and associated with accumulation of residual bodies and glycogen in hearts of 60-week-old knockin mice. We found that Akt-mTORC1 (mammalian target of rapamycin complex 1) signaling was increased, and treatment with 2.24 mg/kg·d rapamycin or 40{\%} caloric restriction for 9 weeks partially rescued cardiomyopathy or heart failure and restored autophagic flux in knockin mice.CONCLUSIONS: Altogether, we found that (1) autophagy is altered in patients with HCM carrying MYBPC3 mutations, (2) autophagy is impaired in Mybpc3-targeted knockin mice, and (3) activation of autophagy ameliorated the cardiac disease phenotype in this mouse model. We propose that activation of autophagy might be an attractive option alone or in combination with another therapy to rescue HCM caused by MYBPC3 mutations.",
keywords = "autophagy, caloric restriction, cardiomyopathy, hypertrophy, rapamycin",
author = "Singh, {Sonia R.} and Zech, {Antonia T.L.} and Birgit Geertz and Silke Reischmann-D{\"u}sener and Hanna Osinska and Maksymilian Prondzynski and Elisabeth Kr{\"a}mer and Qinghang Meng and Charles Redwood and {van der Velden}, Jolanda and Jeffrey Robbins and Saskia Schlossarek and Lucie Carrier",
year = "2017",
month = "10",
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doi = "10.1161/CIRCHEARTFAILURE.117.004140",
language = "English",
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Singh, SR, Zech, ATL, Geertz, B, Reischmann-Düsener, S, Osinska, H, Prondzynski, M, Krämer, E, Meng, Q, Redwood, C, van der Velden, J, Robbins, J, Schlossarek, S & Carrier, L 2017, 'Activation of Autophagy Ameliorates Cardiomyopathy in Mybpc3-Targeted Knockin Mice' Circulation. Heart failure, vol. 10, no. 10, e004140. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004140

Activation of Autophagy Ameliorates Cardiomyopathy in Mybpc3-Targeted Knockin Mice. / Singh, Sonia R.; Zech, Antonia T.L.; Geertz, Birgit; Reischmann-Düsener, Silke; Osinska, Hanna; Prondzynski, Maksymilian; Krämer, Elisabeth; Meng, Qinghang; Redwood, Charles; van der Velden, Jolanda; Robbins, Jeffrey; Schlossarek, Saskia; Carrier, Lucie.

In: Circulation. Heart failure, Vol. 10, No. 10, e004140, 01.10.2017.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Activation of Autophagy Ameliorates Cardiomyopathy in Mybpc3-Targeted Knockin Mice

AU - Singh, Sonia R.

AU - Zech, Antonia T.L.

AU - Geertz, Birgit

AU - Reischmann-Düsener, Silke

AU - Osinska, Hanna

AU - Prondzynski, Maksymilian

AU - Krämer, Elisabeth

AU - Meng, Qinghang

AU - Redwood, Charles

AU - van der Velden, Jolanda

AU - Robbins, Jeffrey

AU - Schlossarek, Saskia

AU - Carrier, Lucie

PY - 2017/10/1

Y1 - 2017/10/1

N2 - BACKGROUND: Alterations in autophagy have been reported in hypertrophic cardiomyopathy (HCM) caused by Danon disease, Vici syndrome, or LEOPARD syndrome, but not in HCM caused by mutations in genes encoding sarcomeric proteins, which account for most of HCM cases. MYBPC3, encoding cMyBP-C (cardiac myosin-binding protein C), is the most frequently mutated HCM gene.METHODS AND RESULTS: We evaluated autophagy in patients with HCM carrying MYBPC3 mutations and in a Mybpc3-targeted knockin HCM mouse model, as well as the effect of autophagy modulators on the development of cardiomyopathy in knockin mice. Microtubule-associated protein 1 light chain 3 (LC3)-II protein levels were higher in HCM septal myectomies than in nonfailing control hearts and in 60-week-old knockin than in wild-type mouse hearts. In contrast to wild-type, autophagic flux was blunted and associated with accumulation of residual bodies and glycogen in hearts of 60-week-old knockin mice. We found that Akt-mTORC1 (mammalian target of rapamycin complex 1) signaling was increased, and treatment with 2.24 mg/kg·d rapamycin or 40% caloric restriction for 9 weeks partially rescued cardiomyopathy or heart failure and restored autophagic flux in knockin mice.CONCLUSIONS: Altogether, we found that (1) autophagy is altered in patients with HCM carrying MYBPC3 mutations, (2) autophagy is impaired in Mybpc3-targeted knockin mice, and (3) activation of autophagy ameliorated the cardiac disease phenotype in this mouse model. We propose that activation of autophagy might be an attractive option alone or in combination with another therapy to rescue HCM caused by MYBPC3 mutations.

AB - BACKGROUND: Alterations in autophagy have been reported in hypertrophic cardiomyopathy (HCM) caused by Danon disease, Vici syndrome, or LEOPARD syndrome, but not in HCM caused by mutations in genes encoding sarcomeric proteins, which account for most of HCM cases. MYBPC3, encoding cMyBP-C (cardiac myosin-binding protein C), is the most frequently mutated HCM gene.METHODS AND RESULTS: We evaluated autophagy in patients with HCM carrying MYBPC3 mutations and in a Mybpc3-targeted knockin HCM mouse model, as well as the effect of autophagy modulators on the development of cardiomyopathy in knockin mice. Microtubule-associated protein 1 light chain 3 (LC3)-II protein levels were higher in HCM septal myectomies than in nonfailing control hearts and in 60-week-old knockin than in wild-type mouse hearts. In contrast to wild-type, autophagic flux was blunted and associated with accumulation of residual bodies and glycogen in hearts of 60-week-old knockin mice. We found that Akt-mTORC1 (mammalian target of rapamycin complex 1) signaling was increased, and treatment with 2.24 mg/kg·d rapamycin or 40% caloric restriction for 9 weeks partially rescued cardiomyopathy or heart failure and restored autophagic flux in knockin mice.CONCLUSIONS: Altogether, we found that (1) autophagy is altered in patients with HCM carrying MYBPC3 mutations, (2) autophagy is impaired in Mybpc3-targeted knockin mice, and (3) activation of autophagy ameliorated the cardiac disease phenotype in this mouse model. We propose that activation of autophagy might be an attractive option alone or in combination with another therapy to rescue HCM caused by MYBPC3 mutations.

KW - autophagy

KW - caloric restriction

KW - cardiomyopathy

KW - hypertrophy

KW - rapamycin

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U2 - 10.1161/CIRCHEARTFAILURE.117.004140

DO - 10.1161/CIRCHEARTFAILURE.117.004140

M3 - Article

VL - 10

JO - Circulation. Heart failure

JF - Circulation. Heart failure

SN - 1941-3289

IS - 10

M1 - e004140

ER -

Singh SR, Zech ATL, Geertz B, Reischmann-Düsener S, Osinska H, Prondzynski M et al. Activation of Autophagy Ameliorates Cardiomyopathy in Mybpc3-Targeted Knockin Mice. Circulation. Heart failure. 2017 Oct 1;10(10). e004140. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004140