Enhanced autophagy ameliorates cardiac proteinopathy

J Clin Invest. 2013 Dec;123(12):5284-97. doi: 10.1172/JCI70877. Epub 2013 Nov 1.


Basal autophagy is a crucial mechanism in cellular homeostasis, underlying both normal cellular recycling and the clearance of damaged or misfolded proteins, organelles and aggregates. We showed here that enhanced levels of autophagy induced by either autophagic gene overexpression or voluntary exercise ameliorated desmin-related cardiomyopathy (DRC). To increase levels of basal autophagy, we generated an inducible Tg mouse expressing autophagy-related 7 (Atg7), a critical and rate-limiting autophagy protein. Hearts from these mice had enhanced autophagy, but normal morphology and function. We crossed these mice with CryABR120G mice, a model of DRC in which autophagy is significantly attenuated in the heart, to test the functional significance of autophagy activation in a proteotoxic model of heart failure. Sustained Atg7-induced autophagy in the CryABR120G hearts decreased interstitial fibrosis, ameliorated ventricular dysfunction, decreased cardiac hypertrophy, reduced intracellular aggregates and prolonged survival. To determine whether different methods of autophagy upregulation have additive or even synergistic benefits, we subjected the autophagy-deficient CryABR120G mice and the Atg7-crossed CryABR120G mice to voluntary exercise, which also upregulates autophagy. The entire exercised Atg7-crossed CryABR120G cohort survived to 7 months. These findings suggest that activating autophagy may be a viable therapeutic strategy for improving cardiac performance under proteotoxic conditions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / physiology*
  • Autophagy-Related Protein 7
  • Cardiomyopathies / genetics
  • Cardiomyopathies / metabolism*
  • Cardiomyopathies / pathology
  • Crosses, Genetic
  • Disease Models, Animal
  • Doxorubicin / pharmacology
  • Gene Expression Regulation / drug effects
  • Heart Failure / etiology
  • Heart Failure / metabolism
  • Heart Failure / pathology
  • Heart Failure / therapy
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / biosynthesis
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / physiology
  • Muscle Proteins / metabolism*
  • Muscular Dystrophies / genetics
  • Muscular Dystrophies / metabolism*
  • Muscular Dystrophies / pathology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Physical Conditioning, Animal
  • Proteostasis Deficiencies / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Ventricular Dysfunction / prevention & control
  • alpha-Crystallin B Chain / genetics


  • Atg7 protein, mouse
  • Cryab protein, mouse
  • Microtubule-Associated Proteins
  • Muscle Proteins
  • Recombinant Fusion Proteins
  • alpha-Crystallin B Chain
  • Doxorubicin
  • Autophagy-Related Protein 7

Supplementary concepts

  • Myopathy, Myofibrillar, Desmin-Related