Atrogin-1 deficiency promotes cardiomyopathy and premature death via impaired autophagy.
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.
Tania
T
Zaglia
Giulia
G
Milan
Aaron
A
Ruhs
Mauro
M
Franzoso
Enrico
E
Bertaggia
Nicola
N
Pianca
Andrea
A
Carpi
Pierluigi
P
Carullo
Paola
P
Pesce
David
D
Sacerdoti
Cristiano
C
Sarais
Daniele
D
Catalucci
Marcus
M
Krüger
Marco
M
Mongillo
Marco
M
Sandri
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology*; D009202:Cardiomyopathies / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004562:Electrocardiography; D059865:Endoplasmic Reticulum Stress; D056827:Endosomal Sorting Complexes Required for Transport / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D017180:Tachycardia, Ventricular / Q000209:etiology; D025801:Ubiquitin / Q000378:metabolism; D056811:Unfolded Protein Response
C525139:CHMP2B protein, mouse; D056827:Endosomal Sorting Complexes Required for Transport; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D025801:Ubiquitin; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; D046988:Proteasome Endopeptidase Complex