Abstract 11097: Voluntary Exercise and Atg7 Overexpression Induced Autophagy Ameliorates Cardiac Proteinopathy
Backgrounds: Basal autophagy is a crucial mechanism in cellular homeostasis, underlying normal recycling and the clearance of damaged or misfolded proteins, organelles and aggregates. Cardiac proteinopathies, such as desmin-related cardiomyopathy (DRC), which can lead to accumulations of misfolded proteins, can also trigger alterations in cardiomyocyte autophagy that might significantly impact on both adaptive and maladaptive processes. However, a mouse model of cardiac specific-inducible autophagy is lacking and the effects of acute or chronic increases in autophagy remain unclear.
Hypothesis: To determine whether enhanced levels of autophagy induced by either autophagic transgene expression or voluntary exercise can ameliorate DRC.
Methods and Results: We induced high levels of autophagy by generating an inducible-transgenic mouse expressing Atg7, a critical, rate-limiting autophagy protein. When transgene expression was induced, the transgenically modified hearts showed enhanced autophagy but maintained normal morphology and function. We crossed these mice with CryABR120G mice, a model of DRC that has abnormally low levels of cardiac autophagy, to test the functional significance of autophagy activation in a proteotoxic model of heart failure. Sustained Atg7-induced autophagy in CryABR120G hearts decreased interstitial fibrosis, ameliorated ventricular dysfunction, attenuated cardiac hypertrophy, reduced intracellular aggregates and prolonged survival times by 40%. To determine if different methods of up-regulating autophagy would lead to additive or even synergistic benefits, we subjected the autophagy deficient CryABR120G mice and Atg7xCryABR120G mice to voluntary exercise as it also up-regulates autophagy. The exercised, Atg7xCryABR120G cohort showed 100% survival at 7 months, by which time all CryABR120G mice have died.
Conclusions: These findings suggest that activating autophagy may be therapeutic and improved cardiac performance under proteotoxic conditions.
- © 2013 by American Heart Association, Inc.