Red Blood Cell Creatine as a Biomarker of Systemic Creatine Transport Capacity and Tissue Bioavailability: Toward a Multi-Compartment Framework of Human Bioenergetics.

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 suggests RBC creatine responses may more closely parallel skeletal muscle creatine accrual than brain creatine, where additional transport constraints imposed by the blood-brain barrier limit direct extrapolation. Therefore, RBC creatine currently should not be regarded as a surrogate for brain creatine, but it may serve as an accessible, time-integrated indicator of systemic creatine transport and distribution. Red blood cell creatine represents a promising but underused biomarker within a multicompartment model of creatine bioavailability. Integrating RBC creatine with circulating markers, direct tissue creatine measurements, and functional bioenergetic outcomes may provide a physiologically grounded and scalable approach to characterizing creatine transport, tissue delivery, and interindividual responsiveness. Prospective studies simultaneously measuring plasma, RBC, and tissue creatine are needed to establish the incremental predictive and clinical value of RBC creatine.