Low-Dose Creatine Supplementation Lowers Plasma Guanidinoacetate, but Not Plasma Homocysteine, in a Double-Blind, Randomized, Placebo-Controlled Trial

Abstract

Background: Creatine synthesis from guanidinoacetate consumes ~50% of s-adenosylmethionine (SAM)-derived methyl groups, accounting for an equivalent proportion of s-adenosylhomocysteine (SAH) and total homocysteine (tHcys) synthesis. Dietary creatine inhibits the synthesis of guanidinoacetate, thereby lowering plasma tHcys in rats.

Objective: We tested the hypotheses that creatine supplementation lowers plasma guanidinoacetate, increases blood SAM, lowers blood SAH, and lowers plasma tHcys.

Methods: Bangladeshi adults were randomly assigned to receive 1 of 4 treatments for 12 wk: placebo (n = 101), 3 g/d creatine (Cr; n = 101), 400 μg/d folic acid (FA; n = 153), or 3 g/d creatine plus 400 μg/d folic acid (Cr+FA; n = 103). The outcomes of plasma guanidinoacetate and tHcys, as well as whole blood SAM and SAH, were analyzed at baseline and week 12 by HPLC. Treatment effects of creatine supplementation were examined with the use of the group comparisons of Cr vs. placebo and Cr+FA vs. FA.

Results: Plasma guanidinoacetate declined by 10.6% (95% CI: 4.9, 15.9) in the Cr group while increasing nonsignificantly in the placebo group (3.7%; 95% CI: -0.8, 8.5) (Pgroup difference = 0.0002). Similarly, plasma guanidinoacetate declined by 9.0% (95% CI: 3.4, 14.2) in the Cr+FA group while increasing in the FA group (7.0%; 95% CI: 2.0, 12.2) (Pgroup difference < 0.0001). Plasma tHcys declined by 23.4% (95% CI: 19.5, 27.1) and 21.0% (95% CI: 16.4, 25.2) in the FA and Cr+FA groups, respectively (Pgroup difference = 0.41), with no significant changes in the placebo or Cr groups (Pgroup difference = 0.35). A decrease in guanidinoacetate over time was associated with a decrease in tHcys over time in the Cr+FA group (β = 0.30; 95% CI: 0.17, 0.43; P < 0.0001).

Conclusions: Our findings indicate that whereas creatine supplementation downregulates endogenous creatine synthesis, this may not on average lower plasma tHcys in humans. However, tHcys did decrease in those participants who experienced a decline in plasma guanidinoacetate while receiving creatine plus folic acid supplementation. This trial was registered at clinicaltrials.gov as NCT01050556.

Keywords: Bangladesh; RCT; creatine; folate; folic acid; guanidinoacetate; homocysteine; hyperhomocysteinemia; s-adenosylmethionine.

Conflict of interest statement

BA Peters, MN Hall, X Liu, F Parvez, AB Siddique, H Shahriar, MN Uddin, T Islam, V Ilievski, JH Graziano, and MV Gamble, no conflicts of interest.

© 2015 American Society for Nutrition.

Figures

FIGURE 1

Overview of Cr metabolism and the methionine cycle. In the first, rate-limiting step of Cr biosynthesis, GAA is formed from arginine and glycine by AGAT (30); in the rat, this reaction occurs primarily in the kidney (36). Dietary Cr (primarily from meat) leads to pretranslational inhibition of AGAT (12), thereby inhibiting endogenous Cr biosynthesis. GAA is transported to the liver, where it is methylated by GAMT to generate Cr, with SAM as the methyl donor (30). The byproduct of this methylation reaction (and others) is SAH. SAH is hydrolyzed to generate Hcys. Hcys can be remethylated to methionine by MS, with 5-mTHF as the methyl donor, or it can be directed to the transsulfuration pathway through which it is ultimately catabolized. 5-mTHF also reduces Hcys by inhibition of GNMT, a major consumer of SAM (5). Cr, whether derived from endogenous biosynthesis or dietary sources, is transported to tissues with high energy requirements such as the skeletal muscle, heart, and brain, where it is phosphorylated to PCr (30). PCr is used for the regeneration of ATP during intensive exercise. Cr and PCr are converted nonenzymatically at a constant rate to Crn, which is then excreted in the urine (30). AGAT, arginine:glycine amidinotransferase; Cr, creatine; Crn, creatinine; GAA, guanidinoacetate; GAMT, guanidinoacetate methyltransferase; GNMT, glycine N-methyltransferase; Hcys, homocysteine; MS, methionine synthase; PCr, phosphorylcreatine; SAH, s-adenosylhomocysteine; SAM, s-adenosylmethionine; Sar, sarcosine; 5-mTHF, 5-methyltetrahydrofolate. Drawings by Brandilyn A Peters; reproduced with permission.

FIGURE 2

Within-person changes in plasma GAA and tHcys from baseline to week 12 by treatment group in Bangladeshi adults participating in a folic acid and creatine randomized, controlled trial. Plots display the within-person change in plasma GAA (A) or plasma tHcys (B) by treatment group. Individual participants were sorted by baseline concentration on the x-axis. Rising and falling vertical bars indicate each participant’s increase or decrease, respectively, in GAA or tHcys from that participant’s baseline. One outlier was excluded from the tHcys placebo plot (baseline tHcys = 107 μmol/L, week 12 tHcys = 97 μmol/L) for better visual resolution on the y-axis. GAA, guanidinoacetate; tHcys, total homocysteine.