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Co-administration of creatine and

guanidinoacetic acid for augmented tissue
bioenergetics: A novel...

Article in Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · July 2017

DOI: 10.1016/j.biopha.2017.04.075

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 Biomedicine & Pharmacotherapy 91 (2017) 238–240

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Opinion Paper

Co-administration of creatine and guanidinoacetic acid for augmented

tissue bioenergetics: A novel approach?
Sergej M. Ostojica,b,*
a
Faculty of Sport and PE, University of Novi Sad, Novi Sad, Serbia
b
University of Belgrade School of Medicine, Belgrade, Serbia

A R T I C L E I N F O A B S T R A C T

Article history:
Received 20 February 2017 A confined absorption of exogenous creatine through creatine transporter (CRT1) seems to hamper its
Received in revised form 16 April 2017 optimal uptake in bioenergetical deficits. Co-administration of guanidinoacetic acid (GAA) along with
Accepted 17 April 2017 creatine could target other transport channels besides CRT1, and supremely improve cellular levels of
creatine. This innovative approach might tackle tissues difficult to reach with conventional creatine
Keywords: interventions, providing a potentially more effective and safe mixture in clinical pharmacology and
Guanidinoacetic acid therapeutics.
Creatine transporter © 2017 Elsevier Masson SAS. All rights reserved.
SLC6A6
GAT2

1. Introduction limitations of creatine are highly required to upsurge tissue

Inadequate tissue bioenergetics remains an important thera-
peutic target in many disorders that affect organs with high-energy
output, including the brain, liver, heart or skeletal muscle. Several
management strategies have been developed to tackle poor
bioenergetics (as diagnosed by low tissue creatine levels), with
oral creatine often suggested as a practical intervention to improve
clinical biomarkers and patient-reported outcomes in different
pathologies [1]. However, creatine use seems to be somewhat
creatine levels. Co-administration of guanidinoacetic acid (GAA;
also known as glycocyamine or betacyamine) with creatine
perhaps provide such a novel approach for augmented tissue
bioenergetics, since GAA might tackle other transport vehicles
Creatine
SLC6A8

limited in terms of its transportability, utilization or performance

in target tissues. For example, the use of creatine has so far proved
disappointing in neurodegenerative diseases with bioenergetical
deficit, such as Parkinson's disease, Huntington's disease, and
amyotrophic lateral sclerosis [2]. This perhaps happens due to
SLC6A6!

GAMT
limited cellular uptake of exogenous creatine, which is mainly GAA GAA Creatine
controlled by a saturable creatine transporter (CRT1 or SLC6A8).
CRT1 is expressed in high amounts in the brain, intestine and SAM SAH
ATP
skeletal muscle, where it plays a crucial role in the distribution of
CK
creatine to target tissues. However, provision of extra creatine
GAT2

might be ineffective for augmented cellular uptake since CRT1 ADP

happens to be a bottleneck for creatine transport into the cell [3].
Therefore, interventional practices that overcome transport Phosphocreatine

Circulation Cell

Abbreviations: CRT1, creatine transporter; GAA, guanidinoacetic acid; GAT2,
gamma-aminobutyric acid transporter; SLC6A6, Taurine transporter.
* Corresponding author at: Applied Bioenergetics Lab, Faculty of Sport and
Physical Education, University of Novi Sad, Lovcenska 16, Novi Sad 21000, Serbia.
E-mail address: sergej.ostojic@chess.edu.rs (S.M. Ostojic).
Fig. 1. Transport channels for creatine and GAA. Abbreviations: GAA, guanidinoa-
cetic acid; SCL6A8, creatine transporter; SLC6A6, taurine transporter; GAT2,
gamma-aminobutyric acid transporter; GAMT, guanidinoacetate N-methyltrans-
ferase; SAM, S-adenosyl methionine; SAH, S-adenosyl homocysteine; CK, creatine
kinase; ATP, adenosine triphosphate; ADP, adenosine diphosphate.

http://dx.doi.org/10.1016/j.biopha.2017.04.075
0753-3322/© 2017 Elsevier Masson SAS. All rights reserved.
 S.M. Ostojic / Biomedicine & Pharmacotherapy 91 (2017) 238–240
Fig. 2. Possible research topics to be addressed for creatine-plus-GAA mixture.
besides CRT1, and outdo creatine intervention by itself. Here, I
discussed this speculative interventional strategy, and outlined
open questions for potential creatine and GAA co-administration in
clinical pharmacology and therapeutics.
2. Creatine plus GAA: a match made in heaven?
GAA is a direct metabolic forerunner of creatine, with
methylation of GAA to creatine catalyzed by guanidinoacetate
N-methyltransferase. This simple reaction takes place mainly in
the liver, but also in high energy-demanding tissues (e.g. brain,
skeletal muscle, myocardium) [4]. GAA has been shown to
effectively increase tissue levels of creatine after exogenous
administration [5,6], suggesting its important role in cellular
bioenergetics. Besides transported through CRT1, GAA might be
also transferred into the cell via protein carriers for taurine
(SLC6A6) and g-aminobutyric acid (GAT2), and via passive
diffusion through plasmalemma [7]. Comparing to creatine, the
affinity of CRT1 for GAA is  10-fold lower (Km = 269–412 mM),
indicating low potential of GAA to be transported via this channel
when creatine is highly available [8]. However, when CRT1 is
saturated with creatine (i.e. after exogenous administration),
provision of extra GAA might target other channels and boost
cellular levels of GAA and creatine comparing to creatine alone
(Fig. 1). This co-administration strategy might be particularly
effective in cases of advanced bioenergetical needs (e.g. exhaustive
exercise), limited CRT1 density in specific tissues (e.g. blood-brain
barrier), or conditions with finite efficacy of interventional creatine
(e.g. neurodegenerative diseases).
A possible co-administration of creatine and GAA might be a
better strategy comparing to administration of each compound per
se. Besides providing a competitive advantage for enhanced levels
of cellular creatine, a mixture might also diminish side effects
related to isolated GAA administration, such as elevated homo-
cysteine production [9], due to hypohomocysteinemic action of
creatine [10] and lower amounts of GAA to be used. So far, no
clinical or preclinical models, including cellular and animal studies,
have been published that support this concept. However, prelimi-
nary studies in pigs [5] and humans [11] found that dietary GAA
was more effective than creatine per se at enhancing tissue creatine
stores, suggesting possible additive or synergistic effect of a
combination of exogenous GAA with endogenous creatine.
Nevertheless, many practical issues of this approach are not
addressed at the moment (Fig. 2). For example, no pharmacological
profiles of creatine-GAA mixture are described so far neither any
239
credible information is currently available how this combination
affects endogenous synthesis of GAA and creatine. In addition, the
amount of each substance in a mixture is currently unknown.
Perhaps creatine should be available in higher proportions due to
its higher affinity for CRT1 comparing to GAA, and better safety
profiles. Systematic titration studies are needed to define the most
effective creatine-to-GAA ratio in terms of safety and efficacy of
proposed mixture.
3. Conclusion
Creatine plus GAA might be a worthwhile formulation to be
evaluated for enhanced tissue bioenergetics in health and disease,
due to its plausible superiority comparing to individual com-
pounds. Future preclinical and clinical studies are highly war-
ranted to investigate its possible benefits for biomedicine and
clinical practice.
Conflicts of interest
No relevant conflicts of interest.
Funding sources
The Serbian Ministry of Education, Science and Technological
Development (Grant # 175037), and the Provincial Secretariat for
Science and Technological Development (Grant # 114-451-710).
The funders had no role in the writing of the report, and in the
decision to submit the article for publication.
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