Protein phosphatase 2A impairs cardiac uptake of glucose in the mammalian heart

Abstract Protein phosphatase 2A (PP2A) accounts for approximately half of all serine/threonine phosphatase activity in the mammalian heart. We hypothesised that PP2A, through dephosphorylation of key regulatory enzymes, modulates cardiac glucose uptake and metabolism in vivo. Using positron emission tomography (PET), we studied the uptake of 2-[ 18 F]fluoro-2-deoxy-D-glucose ([ 18 F]FDG) in living mice with cardiac-specific overexpression of the catalytic subunit of PP2A (PP2A-TG) as well as in littermate controls (wild-type, WT). Additionally, we analysed the expression of enzymes and transcription factors involved in cardiac glucose metabolism. Cardiac glucose consumption was reduced by 41% ( P < 0.05) in PP2A-TG mice relative to WT. Real-time quantitative polymerase chain reaction analysis revealed decreased gene expression of glycogen synthase 1 (− 26%, P < 0.05), glycogen phosphorylase (− 17%, P < 0.05), Mtor (-22%, P < 0.05), peroxisome proliferator-activated receptor gamma (Pparg), and its coactivator PGC-1α (-41% and − 28% respectively; both P < 0.05) in PP2A-TG hearts. Western blotting demonstrated increased protein expression of phosphoinositide 3-kinase (PI3K, 26%, P < 0.05), reduced expression of glycogen synthase (-34%, P < 0.05) and glycogen phosphorylase (-18%, P < 0.05), and enhanced phosphorylation of AKT (95%, P < 0.05) and glycogen synthase kinase-3β (GSK3β, 22%, P < 0.05) in PP2A-TG hearts. These findings indicate that PP2A impairs cardiac glucose metabolism in vivo through modulation of multiple components of glucose handling, including the PI3K/AKT signalling axis, glycogen metabolism, and PPARγ-dependent transcriptional regulation. The effects of PP2A appear to be predominantly indirect. Elevated PP2A expression may therefore be detrimental in heart failure by compromising myocardial energy production.