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The AMPK 1 R70Q mutant regulates multiple metabolic and growth pathways in neonatal cardiac myocytes

¹Cardiovascular Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; ²Dartmouth Medical School, Hanover, New Hampshire; ³James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Department of Pathology and Laboratory Medicine, University of British Columbia-St Paul's Hospital, Vancouver, British Columbia, Canada; and ⁴Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas

Submitted 13 August 2007 ; accepted in final form 25 September 2007

Although mutations in the -subunit of AMP-activated protein kinase (AMPK) can result in excessive glycogen accumulation and cardiac hypertrophy, the mechanisms by which this occurs have not been well defined. Because >65% of cardiac AMPK activity is associated with the 1-subunit of AMPK, we investigated the effects of expression of an AMPK-activating 1-subunit mutant (1 R70Q) on regulatory pathways controlling glycogen accumulation and cardiac hypertrophy in neonatal rat cardiac myocytes. Whereas expression of 1 R70Q displayed the expected increase in palmitate oxidation rates, rates of glycolysis were significantly depressed. In addition, glycogen synthase activity was increased in cardiac myocytes expressing 1 R70Q, due to both increased expression and decreased phosphorylation of glycogen synthase. The inhibition of glycolysis and increased glycogen synthase activity were correlated with elevated glycogen levels in 1 R70Q-expressing myocytes. In association with the reduced phosphorylation of glycogen synthase, glycogen synthase kinase (GSK)-3β protein and mRNA levels were profoundly decreased in the 1 R70Q-expressing myocytes. Consistent with GSK-3β negatively regulating hypertrophy via inhibition of nuclear factor of activated T cells (NFAT), the dramatic downregulation of GSK-3β was associated with increased nuclear activity of NFAT. Together, these data provide important new information about the mechanisms by which a mutation in the -subunit of AMPK causes altered AMPK signaling and identify multiple pathways involved in regulating both cardiac myocyte metabolism and growth that may contribute to the development of the mutant-associated cardiomyopathy.

adenosine 5'-monophosphate-activated protein kinase; glycogen; metabolism; glycogen synthase kinase-3β

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