AMP-activated protein kinase: How a mistake in energy gauge causes glycogen storage

Michal Ofir*, Edith Hochhauser, Bernardo A. Vidne, Dov Freimark, Michael Arad

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

7 Scopus citations


Mutation in PRKAG2 encoding the g2 subunit of the AMP activated protein kinase (AMPK) cause human cardiomyopathy characterized by hypertrophy, Wolff-Parkinson-White syndrome, conduction system disease and glycogen storage in the myocardium. AMPK is a master metabolic regulator activated by hormones and energy deficient states. A heterotrimer enzyme comprising the catalytic a- and regulatory b-and g-subunits was preserved through evolution and is ubiquitously expressed among mammalian tissues. AMPK is activated by AMP and inhibited by ATP that competes for binding to the regulatory sites on the g-subunit. Upstream kinases which phosphorylate Thr172 on the catalytic subunit activate the enzyme during exercise, ischemia, in response to sympathetic stimulation and hormones such as leptin and adiponectin. AMPK operates by phosphorylating its target proteins such as Acetyl CoA Carboxylase. Its classic functions include decreased fat synthesis in liver and adipose tissues, increased fatty acid oxidation, stimulating muscle glucose uptake and glycolysis. Altogether, these activities serve to restore the cellular and whole body energy balance. Human mutations which disrupt the nucleotide-binding affinity of the g2 subunit lead to loss of inhibition by ATP and inappropriate activate AMPK under resting conditions. As a result, myocytes recruit energy metabolites in excess of demand, causing storage of glycogen. Will AMPK ever emerge as a therapeutic target? Bench experiments suggest its potential in treating diabetes, ischemia and cell cycle regulation but much work is needed until these developments reach the bedside.

Original languageEnglish
Pages (from-to)770-775
Number of pages6
Issue number10
StatePublished - Oct 2007
Externally publishedYes


  • AMP-activated protein kinase
  • Cardiomyopathy
  • Glycogen
  • PRKAG2
  • Storage disease


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