Enhanced autophagy ameliorates cardiac proteinopathy

Shenuarin Bhuiyan, J. Scott Pattison, Hanna Osinska, Jeanne James, James Gulick, Patrick M. McLendon, Joseph A Hill, Junichi Sadoshima, Jeffrey Robbins

Research output: Contribution to journalArticle

159 Scopus citations

Abstract

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 CryAB R120G 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.

Original languageEnglish (US)
Pages (from-to)5284-5297
Number of pages14
JournalJournal of Clinical Investigation
Volume123
Issue number12
DOIs
StatePublished - Dec 2 2013

ASJC Scopus subject areas

  • Medicine(all)

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    Bhuiyan, S., Pattison, J. S., Osinska, H., James, J., Gulick, J., McLendon, P. M., Hill, J. A., Sadoshima, J., & Robbins, J. (2013). Enhanced autophagy ameliorates cardiac proteinopathy. Journal of Clinical Investigation, 123(12), 5284-5297. https://doi.org/10.1172/JCI70877