title: Angiotensin II upregulates protein phosphatase 2Cα and inhibits AMP-activated protein kinase signaling and energy balance leading to skeletal muscle wasting.
abstract: Congestive heart failure and chronic kidney disease are characterized by chronically elevated angiotensin II (Ang II) and muscle wasting. Ang II causes skeletal muscle wasting by reducing appetite and by enhancing catabolism. The serine/threonine kinase AMP-activated protein kinase (AMPK) functions mainly as a sensor of cellular energy status. It is energy sparing and favors ATP generation. We hypothesized that Ang II induces muscle wasting in part by inhibiting AMPK signaling and altering cellular energy balance. Our results show that Ang II infusion in mice reduced gastrocnemius muscle weight by 26% and depleted ATP by 74%. In addition, Ang II upregulated protein phosphatase 2Cα by 2.6-fold and reduced AMPK phosphorylation and signaling in muscle. Importantly, the pharmacological AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside restored AMPK activity to levels of pair-fed controls and reversed Ang II-mediated ATP depletion and muscle wasting. Moreover, 5-aminoimidazole-4-carboxamide ribonucleoside activated Akt and inhibited Ang II-induced increases in E3 ubiquitin ligase expression. These novel results demonstrate critical roles for energy depletion and AMPK inhibition in Ang II-induced skeletal muscle wasting and suggest a therapeutic potential for AMPK activators in diseases characterized by muscle wasting.
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: A Michael
authors.initials: AM
authors.lastname: Tabony
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Sarah
authors.initials: S
authors.lastname: Galvez
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Higashi
authors.forename: Sergiy
authors.initials: S
authors.lastname: Sukhanov
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
authors.forename: William E
authors.initials: WE
authors.lastname: Mitch
authors.forename: Patrice
authors.initials: P
authors.lastname: Delafontaine
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008931:Mitochondria, Muscle / Q000378:metabolism; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000503:physiopathology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D012265:Ribonucleotides; D000804:Angiotensin II; D000620:Aminoimidazole Carboxamide; D000255:Adenosine Triphosphate; D044767:Ubiquitin-Protein Ligases; D055372:AMP-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; C031143:AICA ribonucleotide