Plasma creatine, estimated intramuscular creatine, transcellular gradient and the risk of mortality: Results from the PREVEND study.

Background: Creatine, an endogenous compound essential for energy metabolism and cellular function, has been associated with numerous beneficial effects in sports and overall health. Here, we investigated relationships between plasma creatine concentration, estimated intramuscular creatine concentration, and all-cause mortality in the general population.

Methods: In a Dutch prospective population-based cohort, plasma creatine concentration, 24-h urinary creatinine excretion and muscle mass (assessed with bio-electrical impedance analysis) were measured in 5127 participants. Total creatine pool size, calculated from 24-h creatinine excretion (assuming a 1.7% daily excretion of the total creatine pool), was divided by muscle mass to estimate intramuscular creatine concentrations. Transcellular gradient was calculated as intramuscular concentration divided by plasma concentration. Hazard ratios for mortality per doubling were assessed using multivariable Cox proportional hazard models, adjusting for common cardiovascular risk factors for mortality.

Results: Median plasma creatine concentrations were 41 [30-54] μmol/L in females and 28 [21-38] μmol/L in males. Mean intramuscular creatine concentrations were 30 ± 5.0 mmol/kg in females and 27.4 ± 5.0 mmol/kg in males. Median transcellular creatine gradients were 734 [550-1011] in females and 955 [715-1324] in males. Higher intramuscular creatine concentrations were associated with lower mortality in females (HR (95% CI) = .43 (.2; .66)); with a weaker trend in males (HR (95% CI) = .73 (.53; 1.02)). Plasma creatine concentrations were not associated with mortality.

Conclusion: Higher estimated intramuscular creatine concentrations are strongly associated with lower all-cause mortality in females, with a weaker trend in males. Future research should explore causality, as well as further explore the remarkable sex difference.