Sustained Activation of AMPK Enhances Differentiation of Human iPSC-Derived Cardiomyocytes via Sirtuin Activation

Stem Cell Reports. 2020 Aug 11;15(2):498-514. doi: 10.1016/j.stemcr.2020.06.012. Epub 2020 Jul 9.


Recent studies suggest that metabolic regulation may improve differentiation of cardiomyocytes derived from induced pluripotent stem cells (iPSCs). AMP-activated protein kinase (AMPK) is a master regulator of metabolic activities. We investigated whether AMPK participates in iPSC-derived cardiomyocyte differentiation. We observed that AMPK phosphorylation at Thr172 increased at day 9 but then decreased after day 11 of differentiation to cardiomyocytes. Inhibition of AMPK with compound C significantly reduced mRNA and protein expression of cardiac troponins TNNT2 and TNNI3. Moreover, sustained AMPK activation using AICAR from days 9 to 14 of differentiation increased mRNA and protein expression of both TNNT2 and TNNI3. AICAR decreased acetylation of histone 3 at Lys9 and 56 and histone 4 at Lys16 (known target sites for nuclear-localized sirtuins [SIRT1, SIRT6]), suggesting that AMPK activation enhances sirtuin activity. Sustained AMPK activation during days 9-14 of differentiation induces sirtuin-mediated histone deacetylation and may enhance cardiomyocyte differentiation from iPSCs.

Keywords: AMPK; histone acetylation; iPSC-derived cardiomyocytes; sirtuin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Acetylation
  • Cell Differentiation*
  • Chromatin / metabolism
  • Enzyme Activation
  • Gene Expression Regulation
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism*
  • Lysine / metabolism
  • Models, Biological
  • Myocytes, Cardiac / cytology*
  • NAD / metabolism
  • Phosphorylation
  • Sirtuins / metabolism*


  • Chromatin
  • NAD
  • AMP-Activated Protein Kinases
  • Sirtuins
  • Lysine