Physiological Expression of AMPKγ2RG Mutation Causes Wolff-Parkinson-White Syndrome and Induces Kidney Injury in Mice.
Mutations of the AMP-activated kinase gamma 2 subunit (AMPKγ2), N488I (AMPKγ2NI) and R531G (AMPKγ2RG), are associated with Wolff-Parkinson-White (WPW) syndrome, a cardiac disorder characterized by ventricular pre-excitation in humans. Cardiac-specific transgenic overexpression of human AMPKγ2NIor AMPKγ2RGleads to constitutive AMPK activation and the WPW phenotype in mice. However, overexpression of these mutant proteins also caused profound, non-physiological increase in cardiac glycogen, which might abnormally alter the true phenotype. To investigate whether physiological levels of AMPKγ2NIor AMPKγ2RGmutation cause WPW syndrome and metabolic changes in other organs, we generated two knock-in mouse lines on the C57BL/6N background harboring mutations of human AMPKγ2NIand AMPKγ2RG, respectively. Similar to the reported phenotypes of mice overexpressing AMPKγ2NIor AMPKγ2RGin the heart, both lines developed WPW syndrome and cardiac hypertrophy; however, these effects were independent of cardiac glycogen accumulation. Compared with AMPKγ2WTmice, AMPKγ2NIand AMPKγ2RGmice exhibited reduced body weight, fat mass, and liver steatosis when fed with a high fat diet (HFD). Surprisingly, AMPKγ2RGbut not AMPKγ2NImice fed with an HFD exhibited severe kidney injury characterized by glycogen accumulation, inflammation, apoptosis, cyst formation, and impaired renal function. These results demonstrate that expression of AMPKγ2NIand AMPKγ2RGmutations at physiological levels can induce beneficial metabolic effects but that this is accompanied by WPW syndrome. Our data also reveal an unexpected effect of AMPKγ2RGin the kidney, linking lifelong constitutive activation of AMPK to a potential risk for kidney dysfunction in the context of an HFD.
From the Departments of Cardiometabolic Disease.
Xiaodong
X
Yang
Genetic Engineered Models, and.
John
J
Mudgett
the Institut Clinique de la Souris, PHENOMIN, Centre Européen de Recherche en Biologie et Médecine GIE (Groupement d'Intérêt Economique), CNRS UMR 7104, INSERM U964, Université de Strasbourg, 67404 Illkirch, France, and.
Ghina
G
Bou-About
the Institut Clinique de la Souris, PHENOMIN, Centre Européen de Recherche en Biologie et Médecine GIE (Groupement d'Intérêt Economique), CNRS UMR 7104, INSERM U964, Université de Strasbourg, 67404 Illkirch, France, and.
Marie-France
MF
Champy
the Institut Clinique de la Souris, PHENOMIN, Centre Européen de Recherche en Biologie et Médecine GIE (Groupement d'Intérêt Economique), CNRS UMR 7104, INSERM U964, Université de Strasbourg, 67404 Illkirch, France, and.
Hugues
H
Jacobs
the Laboratory of Neurobiology and Cardiovascular Pharmacology Department, EA 7296, Fédération de Médecine Translationnelle, University of Strasbourg, 67000 Strasbourg, France.
Laurent
L
Monassier
the Institut Clinique de la Souris, PHENOMIN, Centre Européen de Recherche en Biologie et Médecine GIE (Groupement d'Intérêt Economique), CNRS UMR 7104, INSERM U964, Université de Strasbourg, 67404 Illkirch, France, and.
Guillaume
G
Pavlovic
the Institut Clinique de la Souris, PHENOMIN, Centre Européen de Recherche en Biologie et Médecine GIE (Groupement d'Intérêt Economique), CNRS UMR 7104, INSERM U964, Université de Strasbourg, 67404 Illkirch, France, and.
Tania
T
Sorg
the Institut Clinique de la Souris, PHENOMIN, Centre Européen de Recherche en Biologie et Médecine GIE (Groupement d'Intérêt Economique), CNRS UMR 7104, INSERM U964, Université de Strasbourg, 67404 Illkirch, France, and.
Yann
Y
Herault
the Institut Clinique de la Souris, PHENOMIN, Centre Européen de Recherche en Biologie et Médecine GIE (Groupement d'Intérêt Economique), CNRS UMR 7104, INSERM U964, Université de Strasbourg, 67404 Illkirch, France, and.
Benoit
B
Petit-Demoulière
From the Departments of Cardiometabolic Disease.
Ku
K
Lu
From the Departments of Cardiometabolic Disease.
Wen
W
Feng
Kenilworth Chemistry and Modeling Informatics, Merck Research Laboratories (MRL), Kenilworth, New Jersey 07033.
Hongwu
H
Wang
From the Departments of Cardiometabolic Disease.
Li-Jun
LJ
Ma
Genetic Engineered Models, and.
Roger
R
Askew
From the Departments of Cardiometabolic Disease.
Mark D
MD
Erion
From the Departments of Cardiometabolic Disease.
David E
DE
Kelley
From the Departments of Cardiometabolic Disease.
Robert W
RW
Myers
From the Departments of Cardiometabolic Disease.
Cai
C
Li
From the Departments of Cardiometabolic Disease, Hong-Ping_Guan@merck.com.
Hong-Ping
http://orcid.org/0000-0002-2282-3193
HP
Guan
D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009154:Mutation; D051437:Renal Insufficiency / Q000235:genetics* / Q000473:pathology; D014927:Wolff-Parkinson-White Syndrome / Q000235:genetics* / Q000473:pathology
D055372:AMP-Activated Protein Kinases
AMP-activated kinase (AMPK); diabetes; glycogen storage disease; insulin resistance; kidney metabolism; liver metabolism