Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 123, Issue 12, Pages 5284-5297Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI70877
Keywords
-
Categories
Funding
- NIH [P01HL69779, P01HL059408, R01HL05924, R011062927]
- Trans-Atlantic Network of Excellence grant from Le Fondation Leducq
- American Heart Association Postdoctoral Fellowship grants
Ask authors/readers for more resources
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 CryAB(R120G) 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 CryAB(R120G) 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 CryAB(R120G) mice to voluntary exercise, which also upregulates autophagy. The entire exercised Atg7-crossed CryAB(R120G) 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available