Hypoxia decreases creatine uptake in cardiomyocytes, while creatine supplementation enhances HIF activation

Lucia Santacruz, Antonio Jose Luis Arciniegas, Marcus Darrabie, Jose G. Mantilla, Rebecca M. Baron, Dawn E. Bowles, Rajashree Mishra, Danny O. Jacobs

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Creatine (Cr), phosphocreatine (PCr), and creatine kinases (CK) comprise an energy shuttle linking ATP production in mitochondria with cellular consumption sites. Myocytes cannot synthesize Cr: these cells depend on uptake across the cell membrane by a specialized creatine transporter (CrT) to maintain intracellular Cr levels. Hypoxia interferes with energy metabolism, including the activity of the creatine energy shuttle, and therefore affects intracellular ATP and PCr levels. Here, we report that exposing cultured cardiomyocytes to low oxygen levels rapidly diminishes Cr transport by decreasing Vmax and Km. Pharmacological activation of AMP-activated kinase (AMPK) abrogated the reduction in Cr transport caused by hypoxia. Cr supplementation increases ATP and PCr content in cardiomyocytes subjected to hypoxia, while also significantly augmenting the cellular adaptive response to hypoxia mediated by HIF-1 activation. Our results indicate that: (1) hypoxia reduces Cr transport in cardiomyocytes in culture, (2) the cytoprotective effects of Cr supplementation are related to enhanced adaptive physiological responses to hypoxia mediated by HIF-1, and (3) Cr supplementation increases the cellular ATP and PCr content in RNCMs exposed to hypoxia.

Original languageEnglish (US)
Article numbere13382
JournalPhysiological reports
Issue number16
StatePublished - Aug 2017


  • AMP-activated kinase
  • cardiac metabolism
  • creatine
  • hypoxia adaptation
  • membrane transport

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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