Autophagy is an adaptive response in desmin-related cardiomyopathy

Abstract

A missense mutation in the ␣B-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 (CryAB R120G ) triggered a >2-fold increase in cardiomyocyte autophagic activity, and blunting autophagy increased the rate of aggregate accumulation and the abundance of insoluble CryAB R120G -associated aggregates. Cardiomyocyte-restricted overexpression of CryAB R120G 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 CryAB R120G 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.

Autophagy Promotes Intracellular Degradation of Type I Collagen Induced by Transforming Growth Factor (TGF)-β1

“…The role of autophagy as an anti-fibrotic response is intriguing. A recent report by Tannous et al has also shown that heterozygous inactivation of beclin 1 resulted in a 3-fold increase in interstitial fibrosis in a model of severe desmin-related cardiomyopathy (29). The beclin 1 ϩ/Ϫ mice have previously been shown to exhibit ϳ50% reduction in autophagic capacity (26).…”

“…Homozygous deletion of beclin 1 (beclin 1 Ϫ/Ϫ ) exhibits early embryonic lethality (25), while heterozygous deletion (beclin 1 ϩ/Ϫ ) results in increased incidence of spontaneous tumorigenesis (26), abnormal proliferation of mammary epithelial cells and germinal center B lymphocytes (27), and increased susceptibility to neurodegeneration (28). A recent study has shown that heterozygous inactivation of beclin 1 resulted in a 3-fold increase in interstitial fibrosis in a model of severe form of desmin-related cardiomyopathy induced by a missense mutation in the ␣B-crystallin (CryAB) gene (29). In contrast to Beclin 1, the mammalian orthologue of Atg8 comprised by a family of proteins known as microtubule-associated protein 1 light chain 3 (LC3) functions, at least in part, as a structural component in the formation of autophagosomes (30).…”

Proteostasis in cardiac health and disease

“…Autophagy, even more than mTOR, seems to confer both adaptive and maladaptive effects, depend ing on the direction and extent of modulation and on the underlying cardiac disease. Autophagy is, for exam ple, beneficial in the desmin related cardiomyopathy of Cryab R120G mice 180 , but accelerates the pathogenesis of pressure loading induced HF in aortic banded mice 181 . Similarly delicate balances might exist in other organs, so specific modulators of autophagy are anticipated to have serious adverse effects, including suppression of the immune system, lung toxicity, and new onset diabetes [182][183][184] .…”

Aggregate-Prone R120GCRYAB Triggers Multifaceted Modifications of the Thioredoxin System

“…Besides acting directly on the mechanisms involved in aggregate formation, another nonmutually exclusive possibility would be to alter the degradation processes of those three forms of R120GCRYAB (s, ins, agg). The proteasome would selectively handle the soluble form and insoluble small oligomers (34,66), while autophagy would be involved in aggregate destruction (42,59,64,67). In support of this later possibility, BAG3 has recently been shown to stimulate autophagy in a complex with the sHSP HspB8 (8).…”

“…Although the time course of aggregate formation has been briefly reported in transfected cells (9,53,55,59), this process has not been characterized in the hR120GTg mice used in the present study (44). We measured aggregate growth in hR120GTg males from 0.5 to 6 months after birth.…”