Autophagy is an adaptive response in desmin-related cardiomyopathy

P Tannous, H Zhu, JL Johnstone… - Proceedings of the …, 2008 - National Acad Sciences
P Tannous, H Zhu, JL Johnstone, JM Shelton, NS Rajasekaran, IJ Benjamin, L Nguyen
Proceedings of the National Academy of Sciences, 2008National Acad Sciences
A missense mutation in the αB-crystallin (CryAB) gene triggers a severe form of desmin-
related cardiomyopathy (DRCM) characterized by accumulation of misfolded proteins. We
hypothesized that autophagy increases in response to protein aggregates and that this
autophagic activity is adaptive. Mutant CryAB (CryABR120G) triggered a> 2-fold increase in
cardiomyocyte autophagic activity, and blunting autophagy increased the rate of aggregate
accumulation and the abundance of insoluble CryABR120G-associated aggregates …
A missense mutation in the αB-crystallin (CryAB) gene triggers a severe form of desmin-related cardiomyopathy (DRCM) characterized by accumulation of misfolded proteins. We hypothesized that autophagy increases in response to protein aggregates and that this autophagic activity is adaptive. Mutant CryAB (CryABR120G) triggered a >2-fold increase in cardiomyocyte autophagic activity, and blunting autophagy increased the rate of aggregate accumulation and the abundance of insoluble CryABR120G-associated aggregates. Cardiomyocyte-restricted overexpression of CryABR120G in mice induced intracellular aggregate accumulation and systolic heart failure by 12 months. As early as 2 months (well before the earliest declines in cardiac function), we detected robust autophagic activity. To test the functional significance of autophagic activation, we crossed CryABR120G mice with animals harboring heterozygous inactivation of beclin 1, a gene required for autophagy. Blunting autophagy in vivo dramatically hastened heart failure progression with a 3-fold increase in interstitial fibrosis, greater accumulation of polyubiquitinated proteins, larger and more extensive intracellular aggregates, accelerated ventricular dysfunction, and early mortality. This study reports activation of autophagy in DRCM. Further, our findings point to autophagy as an adaptive response in this proteotoxic form of heart disease.
National Acad Sciences