Related Experiment Video
Updated: Feb 21, 2026
Activating Autophagy by Aerobic Exercise in Mice
Published on: February 3, 2017
Activation of Autophagy Ameliorates Cardiomyopathy in Mybpc3-Targeted Knockin Mice
Sonia R Singh1, Antonia T L Zech1, Birgit Geertz1
1From 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.).
Insights
Activating autophagy improves hypertrophic cardiomyopathy (HCM) in a mouse model with MYBPC3 mutations. This suggests autophagy modulation could treat HCM caused by MYBPC3 gene mutations.
Area of Science:
- Cardiovascular Research
- Cell Biology
- Genetics
Background:
- Hypertrophic cardiomyopathy (HCM) is often caused by sarcomeric protein gene mutations, with MYBPC3 being the most frequent.
- While autophagy alterations are known in some HCM types, they haven't been extensively studied in MYBPC3-related HCM.
Purpose of the Study:
- To investigate autophagy alterations in MYBPC3 mutation-associated HCM.
- To assess the therapeutic potential of autophagy modulation in a MYBPC3-based HCM mouse model.
Main Methods:
- Evaluated autophagy markers (LC3-II) and autophagic flux in human HCM samples and a MYBPC3 knockin mouse model.
- Examined the impact of rapamycin and caloric restriction on cardiomyopathy progression and autophagy in knockin mice.
Main Results:
- HCM hearts showed increased LC3-II levels, indicating altered autophagy.
- MYBPC3 knockin mice exhibited impaired autophagic flux, glycogen accumulation, and cardiac dysfunction.
- Rapamycin treatment or caloric restriction partially reversed cardiac dysfunction and restored autophagic flux.
Conclusions:
- Autophagy is demonstrably altered and impaired in MYBPC3 mutation-associated HCM.
- Activating autophagy ameliorated cardiac disease in a preclinical model.
- Targeting autophagy presents a potential therapeutic strategy for MYBPC3-related HCM.
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.
More Related Videos
03:45Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
07:40Protection of H9c2 Myocardial Cells from Oxidative Stress by Crocetin via PINK1/Parkin Pathway-Mediated Mitophagy
Published on: May 26, 2023
