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Atrogin-1 deficiency promotes cardiomyopathy and premature death via impaired autophagy
Tania Zaglia, … , Marco Mongillo, Marco Sandri
Tania Zaglia, … , Marco Mongillo, Marco Sandri
Published May 1, 2014
Citation Information: J Clin Invest. 2014;124(6):2410-2424. https://doi.org/10.1172/JCI66339.
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Research Article Cardiology Article has an altmetric score of 20

Atrogin-1 deficiency promotes cardiomyopathy and premature death via impaired autophagy

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Abstract

Cardiomyocyte proteostasis is mediated by the ubiquitin/proteasome system (UPS) and autophagy/lysosome system and is fundamental for cardiac adaptation to both physiologic (e.g., exercise) and pathologic (e.g., pressure overload) stresses. Both the UPS and autophagy/lysosome system exhibit reduced efficiency as a consequence of aging, and dysfunction in these systems is associated with cardiomyopathies. The muscle-specific ubiquitin ligase atrogin-1 targets signaling proteins involved in cardiac hypertrophy for degradation. Here, using atrogin-1 KO mice in combination with in vivo pulsed stable isotope labeling of amino acids in cell culture proteomics and biochemical and cellular analyses, we identified charged multivesicular body protein 2B (CHMP2B), which is part of an endosomal sorting complex (ESCRT) required for autophagy, as a target of atrogin-1–mediated degradation. Mice lacking atrogin-1 failed to degrade CHMP2B, resulting in autophagy impairment, intracellular protein aggregate accumulation, unfolded protein response activation, and subsequent cardiomyocyte apoptosis, all of which increased progressively with age. Cellular proteostasis alterations resulted in cardiomyopathy characterized by myocardial remodeling with interstitial fibrosis, with reduced diastolic function and arrhythmias. CHMP2B downregulation in atrogin-1 KO mice restored autophagy and decreased proteotoxicity, thereby preventing cell death. These data indicate that atrogin-1 promotes cardiomyocyte health through mediating the interplay between UPS and autophagy/lysosome system and its alteration promotes development of cardiomyopathies.

Authors

Tania Zaglia, Giulia Milan, Aaron Ruhs, Mauro Franzoso, Enrico Bertaggia, Nicola Pianca, Andrea Carpi, Pierluigi Carullo, Paola Pesce, David Sacerdoti, Cristiano Sarais, Daniele Catalucci, Marcus Krüger, Marco Mongillo, Marco Sandri

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Figure 8

CHMP2B knockdown protects atrogin-1 KO hearts from block of autophagy and cardiomyocyte apoptosis.

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CHMP2B knockdown protects atrogin-1 KO hearts from block of autophagy an...
(A) Evaluation of mean CHMP2B fluorescence intensity in cryosections from AAV9-GFP-U6-CHMP2Bsh– and AAV9-GFP–treated atrogin-1 KO mice, costained with antibodies to CHMP2B and GFP. Both control (GFP–) and silenced GFP+ cardiomyocytes were analyzed. Error bars represent SEM (**P < 0.01; n = 800 cardiomyocytes from 4 hearts). CHMP2Bsh cardiomyocytes show a significant decrease in CHMP2B fluorescence, as compared with that of controls. No decrease in CHMP2B fluorescence was observed in cardiomyocytes transduced with control viral vector. (B) 3D reconstruction of a cryosection from an AAV9-GFP-U6-CHMP2Bsh–treated atrogin-1 KO mouse costained with antibodies to CHMP2B and GFP, showing no CHMP2B accumulation in GFP+ cells. The white arrow indicates GFP-negative, nonsilenced cells with CHMP2B aggregates visible. Scale bar: 25 μm. (C and D) Confocal immunofluorescence on cryosections from AAV9-GFP-U6-CHMP2Bsh–treated atrogin-1 KO mice, costained with antibodies to GFP and (C) LC3 or (D) p62, showing no accumulation of LC3 and p62 in GFP+ CHMP2Bsh cardiomyocytes (arrows). Scale bar: 25 μm; 10 μm (inset in C). (E) Evaluation of percentage of p62-accumulating cardiomyocytes in GFP– noninfected and GFP+ CHMP2Bsh cells, showing that CHMP2B silencing prevents p62 accumulation. Error bars represent SEM (*0.01 < P < 0.05; n = 450 cardiomyocytes from 4 hearts). (F) Confocal immunofluorescence on cryosections from AAV9-GFP-U6-CHMP2Bsh–treated atrogin-1 KO mice, costained with antibodies to GFP (blue signal), LC3 (green signal), and LAMP2 (red signal), showing colocalization of LC3 and LAMP2 in GFP+ CHMP2Bsh cardiomyocytes. Asterisks indicate GFP-positive, CHMP2Bsh cardiomyocytes. Section symbols indicate GFP-negative, nonsilenced cardiomyocytes. Higher-magnification views of boxed images appears to the right. Scale bar: 25 μm (costaining images); 5 μm (right colocalization images); 10 μm (left colocalization images). (G) Confocal immunofluorescence on cryosections from AAV9-GFP-U6-CHMP2Bsh–treated atrogin-1 KO mice costained with antibodies to GFP and cleaved caspase-3. Higher-magnification views of boxed images appears to the right. Arrows indicate GFP-negative, nonsilenced cardiomyocytes showing cleaved caspase-3 expression. Scale bar: 50 μm (left 3 images); 20 μm (right-most image).

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