Abstract 1255: Autophagy is an Adaptive Response in Desmin-Related Cardiomyopathy
Background: A missense (R120G) mutation in the gene coding for αB-crystallin (CryAB) triggers a severe, familial form of desmin-related cardiomyopathy (DRCM) characterized by accumulation of aggregated, misfolded proteins. We hypothesized that autophagic activity increases in response to the presence of protein aggregates and that autophagy is adaptive in this setting, directing toxic protein aggregates toward lysosomal degradation.
Methods and Results: In neonatal rat ventricular myocytes (NRVM), mutant CryAB (CryABR120G) triggered robust aggregate formation, whereas CryABWT did not. Further, CryABR120G induced a >2-fold increase in cardiomyocyte autophagic activity as determined by electron microscopy or using a live-cell GFP-LC3 reporter system. Blunting autophagy pharmacologically increased the rate of aggregate accumulation, pointing to a role for autophagy in aggregate clearance. To test this in vivo, we studied mice with cardiomyocyte-restricted over-expression of mutant CryAB. As expected, CryABR120G induced intracellular aggregate accumulation, and systolic heart failure was seen by 12 months of age. As early as 2 months (>6 months before earliest declines in cardiac function), we detected robust autophagic activity and accumulation of autophagosomes. To test for evidence of increased autophagic activity in patients, we studied skeletal muscle biopsies from 5 patients with myofibrillar myopathy, detecting increases in autophagosome abundance and lysosomal markers, consistent with increased flux through autophagic pathways. Finally, to determine the functional role of aggregate-induced myocyte autophagy, we crossed CryABR120G mice with animals harboring heterozygous inactivation of the beclin 1 gene, a gene required for autophagic activity. 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.
Conclusions: This study is the first to report autophagic activity in DRCM. Further, our findings point to autophagy as an adaptive response to this proteotoxic form of heart disease.