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This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/H3456    most recent 00936.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Folmes, K. D. Articles by Dyck, J. R. B. Search for Related Content PubMed PubMed Citation Articles by Folmes, K. D. Articles by Dyck, J. R. B.

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