| First Author | Yang X | Year | 2016 |
| Journal | J Biol Chem | Volume | 291 |
| Issue | 45 | Pages | 23428-23439 |
| PubMed ID | 27621313 | Mgi Jnum | J:237375 |
| Mgi Id | MGI:5812629 | Doi | 10.1074/jbc.M116.738591 |
| Citation | Yang X, et al. (2016) Physiological Expression of AMPKgamma2RG Mutation Causes Wolff-Parkinson-White Syndrome and Induces Kidney Injury in Mice. J Biol Chem 291(45):23428-23439 |
| abstractText | Mutations of the AMP-activated kinase gamma 2 subunit (AMPKgamma2), N488I (AMPKgamma2NI) and R531G (AMPKgamma2RG), are associated with Wolff-Parkinson-White (WPW) syndrome, a cardiac disorder characterized by ventricular pre-excitation in humans. Cardiac-specific transgenic overexpression of human AMPKgamma2NI or AMPKgamma2RG 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 AMPKgamma2NI or AMPKgamma2RG 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 AMPKgamma2NI and AMPKgamma2RG, respectively. Similar to the reported phenotypes of mice overexpressing AMPKgamma2NI or AMPKgamma2RG in the heart, both lines developed WPW syndrome and cardiac hypertrophy; however, these effects were independent of cardiac glycogen accumulation. Compared with AMPKgamma2WT mice, AMPKgamma2NI and AMPKgamma2RG mice exhibited reduced body weight, fat mass, and liver steatosis when fed with a high fat diet (HFD). Surprisingly, AMPKgamma2RG but not AMPKgamma2NI 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 AMPKgamma2NI and AMPKgamma2RG 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 AMPKgamma2RG in the kidney, linking lifelong constitutive activation of AMPK to a potential risk for kidney dysfunction in the context of an HFD. |
