AJP - Heart Calcium Transients and Cell-Sarcomere
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Am J Physiol Heart Circ Physiol (March 16, 2007). doi:10.1152/ajpheart.00002.2007
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Submitted on January 2, 2007
Accepted on March 15, 2007

Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration

Li Zhang1, Huamei He1, and James A Balschi2*

1 Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States
2 Medicine, Brigham and Womens Hospital, Boston, Massachusetts, United States

* To whom correspondence should be addressed. E-mail: jbalschi{at}rics.bwh.harvard.edu.

AMP-activated protein kinase (AMPK) acts as a cellular energy sensor. AMPK responds to an increase in AMP concentration ([AMP]) or AMP/ATP. Metformin and phenformin, which are biguanides, have been reported to increase AMPK activity without increasing AMP/ATP. This study tests the hypothesis that these biguanides increase AMPK activity in the heart by increasing cytosolic [AMP]. Groups of isolated rat hearts (n = 5 - 7 each) were perfused with Krebs-Henseleit (KH) buffer with or without 0.2 mM [phenformin] or 10 mM [metformin]. 31P NMR measured phosphocreatine, ATP, and intracellular pH were used to calculate cytosolic [AMP]. At various times hearts were freeze clamped and assayed for AMPK activity, the phosphorylation of Thr172 on the AMPK {alpha} subunit (AMPK-P) and the phosphorylation of Ser79 on ACC, (ACC-P), an AMPK target. In hearts treated with phenformin for 18 min followed by 20 min of KH, [AMP] began to increase at 26 min; at 36 min AMPK activity was elevated. In hearts treated with metformin, [AMP] was increased at 50 min; at 61 min AMPK activity, AMPK-P, and ACC-P were elevated. HPLC measured total AMP content and total AMP/ATP of metformin treated hearts did not increase. In summary, phenformin and metformin both increase AMPK activity and phosphorylation in the isolated heart. The increase in AMPK activity was always preceded by and correlated with increased cytosolic [AMP]. Total AMP content and total AMP/ATP did not change. Cytosolic [AMP] reported metabolically active AMP that triggered increased AMPK activity but measures of total AMP did not.




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