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PMID: 29021349 Published · ppublish English Journal Article

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

Circulation. Heart failure ·Vol. 10 ·No. 10 ·2017-10-00

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

Abstract

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. 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. 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
MeSH Terms
Animals Autophagy/physiology Cardiomyopathies/genetics,metabolism Cardiomyopathy, Hypertrophic/genetics Carrier Proteins/genetics Disease Models, Animal Gene Knock-In Techniques/methods Genotype Heart Failure/genetics,metabolism Humans Mice, Transgenic Mutation/genetics Myocardium/metabolism Phenotype
Chemicals
Carrier Proteins myosin-binding protein C
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Singh Sonia R
From the Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); Department of Pediatrics, The Heart Institute, The Cincinnati Children's Hospital Medical Center, OH (S.R.S., H.O., Q.M., J.R.); Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.R.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and ICIN-Netherlands Heart Institute, Utrecht (J.v.d.V.).
Zech Antonia T L
From the Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); Department of Pediatrics, The Heart Institute, The Cincinnati Children's Hospital Medical Center, OH (S.R.S., H.O., Q.M., J.R.); Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.R.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and ICIN-Netherlands Heart Institute, Utrecht (J.v.d.V.).
Geertz Birgit
From the Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); Department of Pediatrics, The Heart Institute, The Cincinnati Children's Hospital Medical Center, OH (S.R.S., H.O., Q.M., J.R.); Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.R.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and ICIN-Netherlands Heart Institute, Utrecht (J.v.d.V.).
Reischmann-Düsener Silke
From the Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); Department of Pediatrics, The Heart Institute, The Cincinnati Children's Hospital Medical Center, OH (S.R.S., H.O., Q.M., J.R.); Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.R.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and ICIN-Netherlands Heart Institute, Utrecht (J.v.d.V.).
Osinska Hanna
From the Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); Department of Pediatrics, The Heart Institute, The Cincinnati Children's Hospital Medical Center, OH (S.R.S., H.O., Q.M., J.R.); Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.R.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and ICIN-Netherlands Heart Institute, Utrecht (J.v.d.V.).
Prondzynski Maksymilian
From the Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); Department of Pediatrics, The Heart Institute, The Cincinnati Children's Hospital Medical Center, OH (S.R.S., H.O., Q.M., J.R.); Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.R.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and ICIN-Netherlands Heart Institute, Utrecht (J.v.d.V.).
Krämer Elisabeth
From the Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); Department of Pediatrics, The Heart Institute, The Cincinnati Children's Hospital Medical Center, OH (S.R.S., H.O., Q.M., J.R.); Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.R.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and ICIN-Netherlands Heart Institute, Utrecht (J.v.d.V.).
Meng Qinghang
From the Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); Department of Pediatrics, The Heart Institute, The Cincinnati Children's Hospital Medical Center, OH (S.R.S., H.O., Q.M., J.R.); Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.R.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and ICIN-Netherlands Heart Institute, Utrecht (J.v.d.V.).
Redwood Charles
From the Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); Department of Pediatrics, The Heart Institute, The Cincinnati Children's Hospital Medical Center, OH (S.R.S., H.O., Q.M., J.R.); Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.R.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and ICIN-Netherlands Heart Institute, Utrecht (J.v.d.V.).
van der Velden Jolanda
From the Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); Department of Pediatrics, The Heart Institute, The Cincinnati Children's Hospital Medical Center, OH (S.R.S., H.O., Q.M., J.R.); Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.R.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and ICIN-Netherlands Heart Institute, Utrecht (J.v.d.V.).
Robbins Jeffrey
From the Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); Department of Pediatrics, The Heart Institute, The Cincinnati Children's Hospital Medical Center, OH (S.R.S., H.O., Q.M., J.R.); Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.R.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and ICIN-Netherlands Heart Institute, Utrecht (J.v.d.V.).
Schlossarek Saskia
From the Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); Department of Pediatrics, The Heart Institute, The Cincinnati Children's Hospital Medical Center, OH (S.R.S., H.O., Q.M., J.R.); Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.R.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and ICIN-Netherlands Heart Institute, Utrecht (J.v.d.V.).
Carrier Lucie
From the Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (S.R.S., A.T.L.Z., B.G., S.R.-D., M.P., E.K., S.S., L.C.); Department of Pediatrics, The Heart Institute, The Cincinnati Children's Hospital Medical Center, OH (S.R.S., H.O., Q.M., J.R.); Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.R.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and ICIN-Netherlands Heart Institute, Utrecht (J.v.d.V.). [email protected].
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Article Info
Journal
Circulation. Heart failure
Abbr.
Circ Heart Fail
ISSN
1941-3297
DOI
10.1161/CIRCHEARTFAILURE.117.004140
Email
[email protected]
Published
2017-10-00
Language
English
Region
United States
NLM ID
101479941
PMCID
PMC5679453
Subset
IM
Grants
NHLBI NIH HHS · P01 HL069779 · United States
NHLBI NIH HHS · R01 HL087862 · United States
External Links
PubMed source DOI: 10.1161/CIRCHEARTFAILURE.117.004140 PMC Full Text View journal details
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