Submitted to: American Journal of Physiology - Heart and Circulatory Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/25/2007
Publication Date: 9/28/2007
Citation: Folmes, K.D., Witters, L.A., Allard, M.F., Young, M.E., Dyck, J.R. 2007. The AMPK gamma1 R70Q mutant regulates multiple metabolic and growth pathways in neonatal cardiac myocytes. American Journal of Physiology - Heart and Circulatory Physiology. 293(6):H3456-H3464. Interpretive Summary: In order to pump blood around the body, the heart must burn fuels as a source of energy. Two major sources of energy for the heart are fatty acids and carbohydrates. A protein called AMPK has been implicated as a key controller of heart energy metabolism. The current study investigated whether naturally occurring mutations of the protein AMPK affected heart metabolism. The results show that this mutation of AMPK affected both carbohydrate storage, and the ability of the heart cells to grow. These results improve our understanding of the functions of AMPK in the heart.
Technical Abstract: Although mutations in the gamma-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 gamma1-subunit of AMPK, we investigated the effects of expression of an AMPK-activating gamma1-subunit mutant (gamma1 R70Q) on regulatory pathways controlling glycogen accumulation and cardiac hypertrophy in neonatal rat cardiac myocytes. Whereas expression of gamma1 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 gamma1 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 gamma1 R70Q-expressing myocytes. In association with the reduced phosphorylation of glycogen synthase, glycogen synthase kinase (GSK)-3beta protein and mRNA levels were profoundly decreased in the gamma1 R70Q-expressing myocytes. Consistent with GSK-3beta negatively regulating hypertrophy via inhibition of nuclear factor of activated T cells (NFAT), the dramatic downregulation of GSK-3beta was associated with increased nuclear activity of NFAT. Together, these data provide important new information about the mechanisms by which a mutation in the gamma-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 gamma mutant-associated cardiomyopathy.