A PRKAG2 mutation causes biphasic changes in myocardial AMPK activity and does not protect against ischemia

In Vivo Assessment of Myocardial Glucose Uptake by Positron Emission Tomography in Adults With the PRKAG2 Cardiac Syndrome

“…In addition, increased AMPK activity was correlated to low cardiac glycogen content during the early disease stages, whereas diminished AMPK activity was observed when cardiac glycogen levels were high. 27 Our study provided a snapshot of MGU, a surrogate of AMPK activity, in adult humans with well-developed clinical manifestations of the PRKAG2 cardiac syndrome and demonstrated significantly reduced MGU, which may be explained by decreased AMPK activity as predicted by studies in adult transgenic mice expressing this disease. 10,27 The findings of this study are hypothesis-generating and may be useful in future studies evaluating the effect of altered AMPK activity and disease expression in humans with this genetic syndrome.…”

“…[23][24][25][26] In the adult stage of disease in which excessive glycogen accumulation is present, AMPK activity may be downregulated through this mechanism, leading to loss of AMPK activity as observed in adult mice with advanced disease and explaining the apparent discordant findings reported on the effect of PRKAG2 mutations on AMPK activity in this genetic syndrome. 6,10 In support of this hypothesis, Banerjee et al 27 reported biphasic AMPK activity in transgenic mice expressing the human T400N PRKAG2 mutation, demonstrating an increase of AMPK activity in mice at 2 days to 2 weeks of life and a decrease in AMPK activity in mice during adult life. In addition, increased AMPK activity was correlated to low cardiac glycogen content during the early disease stages, whereas diminished AMPK activity was observed when cardiac glycogen levels were high.…”

Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice

“…In contrast to patients with preexcitation, in which a delta wave is often seen, mouse models with preexcitation show activation patterns that indicate complete activation of the ventricle without involvement of the AV conduction system (35)(36)(37)(38)(39)(40). In mice the AV delay is relatively long compared with the total activation time of the ventricles.…”

Adenosine Monophosphate–Activated Kinase and Its Key Role in Catabolism: Structure, Regulation, Biological Activity, and Pharmacological Activation

“…However, studies have shown that the increased glycogen storage was due to a gain of function mutation in the PRKAG2 gene (Banerjee et al, 2007;Gollob et al, 2001b). Recent evidence from transgenic mouse studies suggest that some PRKAG2 mutations, such as N488I, lead to increased AMPK activity and accumulation of glycogen in myocytes, contributing to cardiac hypertrophy (Arad et al, 2003).…”

“…However, there are conflicting data that show that mice expressing the g2 R302Q variant have reduced AMPK activity when measured with the SAMS peptide (Sidhu et al, 2005), a well established AMPK substrate widely used for determination of AMPK activity (Davies et al, 1989). A similar g2 mutation, T400N, when expressed in transgenic mice, resulted in a biphasic effect of the g2 subunit on cardiac muscle AMPK activity, with increased activity in samples from young mice, but reduced activity later in life (Banerjee et al, 2007). These conflicting findings suggest that the lower AMPK activity observed in older mice might be due to secondary effects of the mutation acquired later in life (Banerjee et al, 2007).…”