Physiological Expression of AMPK2RG Mutation Causes Wolff-Parkinson-White Syndrome and Induces Kidney Injury in Mice

Mutations of the AMP-activated kinase gamma 2 subunit (AMPK2), N488I (AMPK2(NI)) and R531G (AMPK2(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 AMPK2(NI) or AMPK2(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 AMPK2(NI) or AMPK2(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 AMPK2(NI) and AMPK2(RG), respectively. Similar to the reported phenotypes of mice overexpressing AMPK2(NI) or AMPK2(RG) in the heart, both lines developed WPW syndrome and cardiac hypertrophy; however, these effects were independent of cardiac glycogen accumulation. Compared with AMPK2(WT) mice, AMPK2(NI) and AMPK2(RG) mice exhibited reduced body weight, fat mass, and liver steatosis when fed with a high fat diet (HFD). Surprisingly, AMPK2(RG) but not AMPK2(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 AMPK2(NI) and AMPK2(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 AMPK2(RG) in the kidney, linking lifelong constitutive activation of AMPK to a potential risk for kidney dysfunction in the context of an HFD.