Red Blood Cell Creatine as a Biomarker of Systemic Creatine Transport Capacity and Tissue Bioavailability: Toward a Multi-Compartment Framework of Human Bioenergetics
Abstract
Direct assessment of tissue creatine in humans remains technically demanding and resource intensive, creating a need for scalable peripheral biomarkers that provide insight into creatine transport and tissue bioavailability. Red blood cell (RBC) creatine is influenced by circulating creatine availability, transporter-mediated uptake, and erythrocyte turnover, but its potential role within the broader physiology of creatine distribution has not been clearly defined. This narrative review evaluates the physiological basis and translational potential of RBC creatine as an intermediate biomarker within a multicompartment framework of human creatine metabolism, bridging systemic creatine availability and tissue-level bioenergetic function. Evidence on RBC creatine kinetics, erythrocyte turnover, creatine transporter biology, creatine supplementation, and tissue creatine accumulation was integrated to examine the determinants of RBC creatine and its potential relationship to systemic and tissue-specific creatine bioavailability. Unlike plasma creatine, which predominantly reflects short-term exposure, RBC creatine integrates circulating creatine availability, transporter-mediated uptake, and erythrocyte age over time. SLC6A8 expression is markedly enriched in erythroid cells (∼32 normalized counts per million [nCPM]) compared with other circulating blood cells (<1.5 nCPM), supporting a high-capacity creatine transport phenotype established during erythropoiesis. Available evidence…
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