| Autophagy is a cellular pathway involved in protein and organelle degradation. Recent findings suggest that selective autophagy disposes of protein aggregates and damaged organelles to carry out the protein quality control. Two recent studies have suggested an important role of autophagy in protection against alphaB-crystallin- based (CryABR120G) desmin-related cardiomyopathies (DRC) but this has not been demonstrated in mutant desmin-based DRC. Moreover, mechanisms regulating autophagy in cardiac proteinopathy remain unclear.;To test the hypothesis that autophagic activity is activated in a mouse model of mutant desmin-based DRC, an autophagosome reporter GFP-LC3 was used and changes in LC3-II protein levels in response to lysosomal inhibition were assessed. The results revealed significantly increased autophagic flux in mouse hearts with transgenic overexpression of a mutant desmin. Similarly, autophagic flux was increased in cultured neonatal rat ventricular myocytes (NRVMs) overexpressing the mutant desmin or CryABR120G. Moreover, autophagy was induced by pharmacological proteasome inhibition both in cultured cardiomyocytes and in intact mice.;In the NRVMs, the ability of a comparable level of mutant desmin overexpression to accumulate ubiquitinated proteins is increased by suppression of autophagy with 3-methyladenine, and reduced by enhancement of autophagy with rapamycin. Likewise, histone deacetylase 6 overexpression accelerated the degradation of mutant desmin and reduced the ability of mutant desmin overexpression to accumulate ubiquitinated proteins. However, heterozygous ablation of the beclin1 gene did not change the amounts of ubiquitinated proteins, the aggregation, or the disease progression of DRC mouse models.;Furthermore, p62/SQSTM1 mRNA and protein expression was significantly upregulated in cardiomyocytes by transgenic overexpression of the mutant desmin or CryABR120G both in intact mice and in cultured NRVMs. To test the hypothesis that upregulated p62 plays a role in regulating autophagy during cardiac proteinopathy, p62 RNA interference experiments were performed. In cultured NRVMs overexpressing a misfolded protein, p62 depletion attenuated aggresome formation and LC3 lipidation, exacerbated cell injury, and decreased cell viability.;Thus, increased autophagic activity serves as an adaptive response to increased expression of misfolded proteins in cardiomyocytes. p62 is upregulated in DRC. p62 facilitates aggresome formation and autophagy activation in cardiomyocytes and thereby reduces the toxicity of misfolded proteins to the cells. |
