1. Atrogin-1 deficiency promotes cardiomyopathy and premature death via impaired autophagy
- Author
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Zaglia, Tania, Milan, Giulia, Ruhs, Aaron, Franzoso, Mauro, Bertaggia, Enrico, Pianca, Nicola, Carpi, Andrea, Carullo, Pierluigi, Pesce, Paola, Sacerdoti, David, Sarais, Cristiano, Catalucci, Daniele, Kruger, Marcus, Mongillo, Marco, and Sandri, Marco
- Subjects
Heart diseases -- Risk factors ,Autophagy (Cytology) -- Health aspects ,Heart cells -- Physiological aspects ,Protein research ,Cardiomyopathy -- Risk factors ,Health care industry - 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 musclespecific 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., Introduction Cardiac muscle mass adapts as a consequence of functional requirements. Increased workload, such as during exercise or chronic disease stresses causing pressure overload, induces cardiomyocyte hypertrophy, while hemodynamic unloading [...]
- Published
- 2014
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