Abstract
ABSTRACTIn this study, we have identified a novel member of the AMPK family, namely Sucrose non-fermenting related kinase (Snrk), that is responsible for maintaining cardiac metabolism in mammals. SNRK is expressed in the heart, and brain, and in cell types such as endothelial cells, smooth muscle cells and cardiomyocytes (CMs). Snrk knockout (KO) mice display enlarged hearts, and die at postnatal day 0. Microarray analysis of embryonic day 17.5 Snrk hearts, and blood profile of neonates display defect in lipid metabolic pathways. SNRK knockdown CMs showed altered phospho-acetyl-coA carboxylase and phospho-AMPK levels similar to global and endothelial conditional KO mouse. Finally, adult cardiac conditional KO mouse displays severe cardiac functional defects and lethality. Our results suggest that Snrk is essential for maintaining cardiac metabolic homeostasis, and shows an autonomous role for SNRK during mammalian development.
Highlights
Metabolic tissues require adequate oxygenation for aerobic metabolism
Sucrose non-fermenting related kinase (Snrk) knockout (KO) mouse characterization To assess the role of Snrk in a mammalian model system, we have generated a global Snrk gene knockout in which exon 3 was replaced with a neomycin cassette using homologous recombination (Fig. 1A)
To determine if other metabolic pathways are affected by the loss of Snrk, we examined the expression levels of the fatty acid synthesis marker fatty acid synthase (FAS), the gluconeogenesis marker phosphoenolpyruvate carboxykinase (PEPCK), the glycolysis marker and direct AMPK target phosphorylated phosphofructokinase 2, and did not observe a statistical difference between Snrk KO and WT hearts
Summary
Proteins that participate in both metabolic and angiogenesis pathways are candidate for this mechanism. Two metabolic sensors, AMP-activated protein kinase (AMPK) (Jager et al, 2007) and Silent mating type information regulation 1 (SIRT1) (Rodgers et al, 2005) participate in metabolism and angiogenesis pathways, by directly regulating PGC-1a activity. Master metabolic sensors have been identified, the mechanisms that control the switch in cardiac energy state from embryonic tissue to adult during cardiovascular development are not known. We provide evidence that a novel member of the AMPK family namely sucrose nonfermenting related kinase (SNRK), previously identified as essential for angiogenesis (Chun et al, 2009) is likely involved in this critical step, and maintains metabolic homeostasis via regulation of the phosphorylated acetyl-coA carboxylase (pACC)-phosphorylated AMPK (pAMPK) pathway during this transitional period in development
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