Doxycycline Attenuates Protein Aggregation in Cardiomyocytes and Improves Survival of a Mouse Model of Cardiac Proteinopathy

ObjectivesThe goal of this pre-clinical study was to assess the therapeutic efficacy of doxycycline (Doxy) for desmin-related cardiomyopathy (DRC) and to elucidate the potential mechanisms involved.BackgroundDRC, exemplifying cardiac proteinopathy, is characterized by intrasarcoplasmic protein aggregation and cardiac insufficiency. No effective treatment for DRC is available presently. Doxy was shown to attenuate aberrant intranuclear aggregation and toxicity of misfolded proteins in noncardiac cells and animal models of other proteinopathies.MethodsMice and cultured neonatal rat cardiomyocytes with transgenic (TG) expression of a human DRC-linked missense mutation R120G of αB-crystallin (CryABR120G) were used for testing the effect of Doxy. Doxy was administered via drinking water (6 mg/ml) initiated at 8 or 16 weeks of age.ResultsDoxy treatment initiated at 16 weeks of age significantly delayed the premature death of CryABR120GTG mice, with a median lifespan of 30.4 weeks (placebo group, 25 weeks; p < 0.01). In another cohort of CryABR120GTG mice, Doxy treatment initiated at 8 weeks of age significantly attenuated cardiac hypertrophy in 1 month. Further investigation revealed that Doxy significantly reduced the abundance of CryAB-positive microscopic aggregates, detergent-resistant CryAB oligomers, and total ubiquitinated proteins in CryABR120GTG hearts. In cell culture, Doxy treatment dose-dependently suppressed the formation of both microscopic protein aggregates and detergent-resistant soluble CryABR120Goligomers and reversed the up-regulation of p62 protein induced by adenovirus-mediated CryABR120Gexpression.ConclusionsDoxy suppresses CryABR120G-induced aberrant protein aggregation in cardiomyocytes and prolongs CryABR120G-based DRC mouse survival.