Out with the old
Several cardiomyopathies and age-related cardiac dysfunction are linked to alterations in the ubiquitin proteasome system (UPS), which tags proteins for degradation. In the heart, the UPS is essential to maintain the balance between cardiomyocyte atrophy and hypertrophy. The muscle-specific E3 ubiquitin ligase atrogin-1 is known to promote muscle atrophy by targeting hypertrophy-associated proteins for degradation, although a role for atrogin-1 in cardiac proteostasis is not clear. Tania Zaglia, Giulia Milan, and colleagues at the University of Padova and the Venetian Institute of Molecular Medicine investigated cardiac homeostasis in atrogin-1-deficient mice. Aged animals lacking atrogin-1 exhibited enlarged and abnormally shaped hearts, thickened left ventricular walls, increased fibrosis and apoptosis, and reduced function. Loss of atrogin-1 led to increased ER stress and upregulation of genes involved in the unfolded protein response (UPR). Moreover, autophagy, which is inhibited by the UPR in skeletal muscle, was also repressed in cardiac tissue of atrogin-1 null mice, suggesting that atrogin-1 may target autophagy-related proteins for degradation. Evaluation of cardiac protein turnover in atrogin-1-deficient animals revealed reduced turnover of lysosomal targets, including the endosomal sorting complex III protein CHMP2B. CHMP2B was a direct target of atrogin-1 ubiquitin ligation, and CHMP2B overexpression in WT cardiomyocytes inhibited autophagy. Silencing CHMP2B in atrogin-1 null mice restored markers of autophagy and reduced apoptosis in the heart. The accompanying image displays the accumulation of CHMP2B (red) in atrogin-1 null cardiomyocytes (green).
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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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ISSN: 0021-9738 (print), 1558-8238 (online)