Creatine uptake in brain and skeletal muscle of mice lacking guanidinoacetate methyltransferase assessed by magnetic resonance spectroscopy

Kan, Hermien E.; Meeuwissen, Esther; Asten, Jack J. van; Veltien, Andor; Isbrandt, Dirk; Heerschap, Arend

doi:10.1152/japplphysiol.01327.2006

Cited by 26 publications

(32 citation statements)

References 46 publications

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“…In vivo data confirmed this hypothesis: the blood to brain transport of Cr through BBB is effective in rats and mice but is relatively inefficient (Ohtsuki et al 2002;Perasso et al 2003), and long-term treatment of AGAT-and GAMT-deficient patients with high doses of Cr allows only a slow and in most cases partial replenishment of their brain Cr pools (Stöckler et al 2007;Schulze and Battini 2007). Similarly, GAMT -/-KO mice treated with high doses of Cr replenish their brain Cr, but only slowly (Kan et al 2007). The effective but limited entry of Cr from blood to CNS through MCEC but without going through astrocytes may occur through the limited surface of CNS microcapillary endothelium that is free of astrocytic feet ( Fig.…”

Section: Creatine In Cns: Endogenous Synthesis Versus Uptake From Permentioning

confidence: 66%

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

et al. 2011

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Creatine deficiency syndromes, due to deficiencies in AGAT, GAMT (creatine synthesis pathway) or SLC6A8 (creatine transporter), lead to complete absence or very strong decrease of creatine in CNS as measured by magnetic resonance spectroscopy. Brain is the main organ affected in creatine-deficient patients, who show severe neurodevelopmental delay and present neurological symptoms in early infancy. AGAT-and GAMT-deficient patients can be treated by oral creatine supplementation which improves their neurological status, while this treatment is inefficient on SLC6A8-deficient patients. While it has long been thought that most, if not all, of brain creatine was of peripheral origin, the past years have brought evidence that creatine can cross blood-brain barrier, however, only with poor efficiency, and that CNS must ensure parts of its creatine needs by its own endogenous synthesis. Moreover, we showed very recently that in many brain structures, including cortex and basal ganglia, AGAT and GAMT, while found in every brain cell types, are not coexpressed but are rather expressed in a dissociated way. This suggests that to allow creatine synthesis in these structures, guanidinoacetate must be transported from AGAT-to GAMT-expressing cells, most probably through SLC6A8. This new understanding of creatine metabolism and transport in CNS will not only allow a better comprehension of brain consequences of creatine deficiency syndromes, but will also contribute to better decipher creatine roles in CNS, not only in energy as ATP regeneration and buffering, but also in its recently suggested functions as neurotransmitter or osmolyte.

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Section: Creatine In Cns: Endogenous Synthesis Versus Uptake From Permentioning

confidence: 66%

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

et al. 2011

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“…In brain, 1 H MR specra were also recorded using an elliptical 1 H surface coil (15 × 11 mm) from a 2.2 mm × 2 mm × 2 mm voxel located partly in thalamus and hippocampus (STEAM, TE = 15 ms, mixing time (TM) = 10 ms, TR = 5 s, 256 averages; Kan et al 2007). Multislice gradient echo images were acquired in transverse (TR = 4000 ms, TE = 4 ms, 10 slices of 1 mm) and horizontal directions (TR = 4000 ms, TE = 10 ms, 4 slices of 1 mm), avoiding inclusion of ventricles in the volume of interest.…”

Section: Methodsmentioning

confidence: 99%

Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake

Nabuurs

Choe

Veltien

et al. 2013

The Journal of Physiology

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Key points• Creatine (Cr) plays an important role in muscle energy homeostasis as a substrate in the creatine kinase phosphoryl exchange reaction, but the consequences of creatine depletion are incompletely understood.• We assessed the morphological, metabolic and functional consequences of systemic creatine depletion on skeletal muscle in a mouse model with deficiency of an essential enzyme in the biosynthesis of creatine (AGAT −/− mice).• We show that Cr depletion leads to several metabolic abnormalities in muscle, including reduced ATP, increased inorganic phosphate levels and reduced activities of proton-pumping respiratory chain enzymes and an elevated glycolytic contribution in ischaemic circumstances.• The Cr-depleted muscle suffers from reduced grip strength, severe atrophy and abnormal mitochondrial structures, increased overall mitochondrial content and an increased number of lipid droplets.• Oral Cr administration led to rapid accumulation in skeletal muscle (faster than in brain) and reversed all the muscle abnormalities, revealing that the condition of the AGAT −/− mice can be switched between Cr deficient and normal simply by dietary manipulation.Abstract Creatine (Cr) plays an important role in muscle energy homeostasis by its participation in the ATP-phosphocreatine phosphoryl exchange reaction mediated by creatine kinase. Given that the consequences of Cr depletion are incompletely understood, we assessed the morphological, metabolic and functional consequences of systemic depletion on skeletal muscle in a mouse model with deficiency of L-arginine:glycine amidinotransferase (AGAT −/− ), which catalyses the first step of Cr biosynthesis. In vivo magnetic resonance spectroscopy showed a near-complete absence of Cr and phosphocreatine in resting hindlimb muscle of AGAT −/− mice. Compared with wild-type, the inorganic phosphate/β-ATP ratio was increased fourfold, while ATP levels were reduced by nearly half. Activities of proton-pumping respiratory chain C. I. Nabuurs and C. U. Choe contributed equally to this work. enzymes were reduced, whereas F 1 F 0 -ATPase activity and overall mitochondrial content were increased. The Cr-deficient AGAT −/− mice had a reduced grip strength and suffered from severe muscle atrophy. Electron microscopy revealed increased amounts of intramyocellular lipid droplets and crystal formation within mitochondria of AGAT −/− muscle fibres. Ischaemia resulted in exacerbation of the decrease of pH and increased glycolytic ATP synthesis. Oral Cr administration led to rapid accumulation in skeletal muscle (faster than in brain) and reversed all the muscle abnormalities, revealing that the condition of the AGAT −/− mice can be switched between Cr deficient and normal simply by dietary manipulation. Systemic creatine depletion results in mitochondrial dysfunction and intracellular energy deficiency, as well as structural and physiological abnormalities. The consequences of AGAT deficiency are more pronounced than those of muscle-specific creatine kinase deficiency, which suggests...

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“…The restricted crossing of peripheral Cr into CNS is also illustrated in Cr orally-treated AGAT-and GAMT-deficient patients who, despite the high doses of Cr used (usually 0.35-2.00 g/kg/day; 20-120 times the normal needs in Cr), replenish their cerebral Cr only slowly, Cr restoration taking months and remaining in most cases only partial (Battini et al 2002;Ganesan et al 1997;Item et al 2001;Schulze 2005;Schulze et al 1998;Stöckler et al 1996). GAMT -/-KO mice treated with the high dose of 2 g/kg/day of Cr normalize their brain Cr after 16 to 35 days of treatment, depending on CNS region (Kan et al 2007). …”

Section: Cr and Gaa Through Bbb And Bcsfb And Within Cnsmentioning

confidence: 99%

“…This interesting case is described in more detail in the following chapter on Cr in immature CNS. A very high dose of creatine (2.0 g/kg/day) was also used in GAMT -/-KO mice to analyze their CNS replenishment in Cr (Kan et al 2007). All these data suggest that BBB has a limited permeability for Cr.…”

Section: Cr and Gaa Through Bbb And Bcsfb And Within Cnsmentioning

confidence: 99%

Creatine and guanidinoacetate transport at blood‐brain and blood‐cerebrospinal fluid barriers

Braissant

2012

J of Inher Metab Disea

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While it was thought that most of cerebral creatine is of peripheral origin, AGAT and GAMT are well expressed in CNS where brain cells synthesize creatine. While the creatine transporter SLC6A8 is expressed by microcapillary endothelial cells (MCEC) at blood-brain barrier (BBB), it is absent from their surrounding astrocytes. This raised the concept that BBB has a limited permeability for peripheral creatine, and that the brain supplies a part of its creatine by endogenous synthesis. This review brings together the latest data on creatine and guanidinoacetate transport through BBB and blood-CSF barrier (BCSFB) with the clinical evidence of AGAT-, GAMT- and SLC6A8-deficient patients, in order to delineate a clearer view on the roles of BBB and BCSFB in the transport of creatine and guanidinoacetate between periphery and CNS, and on brain synthesis and transport of creatine. It shows that in physiological conditions, creatine is taken up by CNS from periphery through SLC6A8 at BBB, but in limited amounts, and that CNS also needs its own creatine synthesis. No uptake of guanidinoacetate from periphery occurs at BBB except under GAMT deficiency, but a net exit of guanidinoacetate seems to occur from CSF to blood at BCSFB, predominantly through the taurine transporter TauT.

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Creatine uptake in brain and skeletal muscle of mice lacking guanidinoacetate methyltransferase assessed by magnetic resonance spectroscopy

Cited by 26 publications

References 46 publications

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake

Creatine and guanidinoacetate transport at blood‐brain and blood‐cerebrospinal fluid barriers

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