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

• Published in: Physiological reports 2017-08, Vol.5 (16), p.e13382-n/a
• Main Authors: Santacruz, Lucia, Arciniegas, Antonio Jose Luis, Darrabie, Marcus, Mantilla, Jose G., Baron, Rebecca M., Bowles, Dawn E., Mishra, Rajashree, Jacobs, Danny O.
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological; Adenosine Triphosphate - metabolism; AMP; AMP‐activated kinase; Animals; cardiac metabolism; Cardiac Muscle; Cardiomyocytes; Cell culture; Cell Hypoxia; Cells, Cultured; Cellular Physiology; Creatine; Creatine - metabolism; Creatine - pharmacology; Energy metabolism; Hypoxia; Hypoxia - metabolism; hypoxia adaptation; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1 - genetics; Hypoxia-Inducible Factor 1 - metabolism; Intracellular; Membrane Physiology; membrane transport; Metabolism and Regulation; Mitochondria; Myocytes; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Original Research; Oxygen - metabolism; Phosphocreatine; Physiology; Protein Kinases - metabolism; Rats; Rats, Sprague-Dawley; RNA, Messenger - genetics; RNA, Messenger - metabolism; Supplements
• ISSN: 2051-817X
• DOI: 10.14814/phy2.13382

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. Creatine, phosphocreatine, and creatine kinases comprise an energy shuttle linking ATP production in mitochondria with cellular consumption sites. Myocytes depend on uptake by a specialized transporter to maintain intracellular creatine levels. Here we demonstrate that hypoxia rapidly decreases creatine transport in cardiomyocytes in culture. Creatine supplementation of cardiomyocytes prior to exposure to hypoxia increases the cellular content of ATP and phosphocreatine and enhances the HIF‐1‐mediated adaptive physiological responses to hypoxia.