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Enhanced autophagy ameliorates cardiac proteinopathy
Md. Shenuarin Bhuiyan, … , Junichi Sadoshima, Jeffrey Robbins
Md. Shenuarin Bhuiyan, … , Junichi Sadoshima, Jeffrey Robbins
Published November 1, 2013
Citation Information: J Clin Invest. 2013;123(12):5284-5297. https://doi.org/10.1172/JCI70877.
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Research Article Cardiology

Enhanced autophagy ameliorates cardiac proteinopathy

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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 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.

Authors

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

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Figure 1

Generation and characterization of cardiomyocyte-specific inducible Atg7-overexpressing mice (Atg7×tTA).

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Generation and characterization of cardiomyocyte-specific inducible Atg7...
(A) Construct design of the binary Tg system regulated by Dox to inducibly overexpress Atg7 in the heart. (B) Representative Western blot showing ATG7 cardiac protein from 2 lines (line 132 and line 151) of 3-month-old Ntg, tTA-Tg, Atg7-Tg, and Atg7×tTA mice without or with Dox (17). (C) Autophagy-related transcript analyses in Atg7×tTA hearts. Shown is a direct groupwise comparison of fold change in mRNA levels in male Atg7×tTA and Ntg hearts at 5 months (n = 3 per group). (D) Western blot showing ATG7 expression and expression levels of autophagy-related proteins in the hearts of 3-month-old Ntg, tTA-Tg, Atg7-Tg, and Atg7×tTA (line 132×55) mice. (E) Quantitation of Atg7 expression for line 132. ***P < 0.001 versus all other groups, Tukey’s post-hoc test.
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