Physiological Expression of AMPKγ2RG Mutation Causes Wolff-Parkinson-White Syndrome and Induces Kidney Injury in Mice.

Date publication

novembre 2016

Journal

The Journal of biological chemistry

Auteurs

Membres identifiés du Cancéropôle Est :
Dr HERAULT Yann , Dr SORG Tania

Tous les auteurs :
Yang X, Mudgett J, Bou-About G, Champy MF, Jacobs H, Monassier L, Pavlovic G, Sorg T, Herault Y, Petit-Demoulière B, Lu K, Feng W, Wang H, Ma LJ, Askew R, Erion MD, Kelley DE, Myers RW, Li C, Guan HP

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/27621313

Résumé

Mutations of the AMP-activated kinase gamma 2 subunit (AMPKγ2), N488I (AMPKγ2(NI)) and R531G (AMPKγ2(RG)), are associated with Wolff-Parkinson-White (WPW) syndrome, a cardiac disorder characterized by ventricular pre-excitation in humans. Cardiac-specific transgenic overexpression of human AMPKγ2(NI) or AMPKγ2(RG) leads 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 AMPKγ2(NI) or AMPKγ2(RG) mutation 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 AMPKγ2(NI) and AMPKγ2(RG), respectively. Similar to the reported phenotypes of mice overexpressing AMPKγ2(NI) or AMPKγ2(RG) in the heart, both lines developed WPW syndrome and cardiac hypertrophy; however, these effects were independent of cardiac glycogen accumulation. Compared with AMPKγ2(WT) mice, AMPKγ2(NI) and AMPKγ2(RG) mice exhibited reduced body weight, fat mass, and liver steatosis when fed with a high fat diet (HFD). Surprisingly, AMPKγ2(RG) but not AMPKγ2(NI) mice 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 AMPKγ2(NI) and AMPKγ2(RG) mutations at physiological levels can induce beneficial metabolic effects but that this is accompanied by WPW syndrome. Our data also reveal an unexpected effect of AMPKγ2(RG) in the kidney, linking lifelong constitutive activation of AMPK to a potential risk for kidney dysfunction in the context of an HFD.

Référence

J. Biol. Chem.. 2016 Nov;291(45):23428-23439