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

Nabuurs, Christine I. H. C.; Choe, Chi‐un; Veltien, Andor; Kan, Hermien E.; Loon, Luc J. C. van; Rodenburg, Richard J.; Matschke, Jakob; Wieringa, Bé; Kemp, Graham J.; Isbrandt, Dirk; Heerschap, Arend

doi:10.1113/jphysiol.2012.241760

Cited by 81 publications

(92 citation statements)

References 107 publications

(160 reference statements)

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“…Mice deficient in the Cr-synthesizing enzyme arginine:gylcine amidinotransferase (AGAT −/− ) show increased mitochondrial enzyme activity in the muscle. Citrate synthase activity is increased in the AGAT −/− mice as well (Nabuurs et al 2013). The increase in mitochondrial activity and citrate synthase support the findings in this study that Cr deficiency increases the number of mitochondria.…”

Section: Discussionmentioning

confidence: 99%

“…Crt −/y mice show significant reductions in ATP both in this study and as shown previously (Russell et al 2014). AGAT deficient mice have reduced muscular ATP (Nabuurs et al 2013). CK knockout mice have ATP reductions during seizures and hypoxia (Kekelidze et al 2001); paradoxically double CK knockout (CK −/− ) mice do not have ATP reductions (in 't Zandt et al 2004).…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism that underlies these changes in currently unknown. Cr and CrT expression have been linked to several the metabolic signaling molecules such as mTOR (Shojaiefard et al 2006), PI3 kinase/AKT (Cunha et al 2015), and AMP activated kinase (Nabuurs et al 2013). Thus, studies to investigate the role of these kinases and signaling pathways in the CrT mediated changes in both mitochondrial function and the overall phenotype of these mice should be considered in future studies.…”

Section: Discussionmentioning

confidence: 99%

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Creatine transporter deficiency leads to increased whole body and cellular metabolism

et al. 2016

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Creatine (Cr) is a guanidino compound required for rapid replenishment of ATP in cells with a high-energy demand. In humans, mutations in the Cr transporter (CRT;SLC6A8) prevent Cr entry into tissue and result in significant intellectual impairment, epilepsy, and aphasia. The lack of Cr on both whole body and cellular metabolism was evaluated in Crt knockout (Crt−/y) mice, a high-fidelity model of human CRT deficiency. Crt−/y mice have reduced body mass however show a two-fold increase in body fat. There was increased energy expenditure in a homecage environment and during treadmill running in Crt−/y mice. Consistent with the increases in whole-body metabolic function, Crt−/y mice show increases in cellular metabolism as well. Mitochondrial respiration increased in skeletal muscle fibers and hippocampal lysates from Crt−/y mice. In addition, Crt−/y mice had increased citrate synthase activity, suggesting a higher number of mitochondria instead of an increase in mitochondrial activity. In order to determine if the increase in respiration was due to increased mitochondrial numbers, we measured oxygen consumption in an equal number of mitochondria from Crt+/y and Crt−/y mice. There were no changes in mitochondrial respiration when normalized to mitochondrial number, suggesting that the increase in respiration observed could be to higher mitochondrial content in Crt−/y mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Creatine transporter deficiency leads to increased whole body and cellular metabolism

et al. 2016

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“…This GAA may then be phosphorylated to produce energy-rich P-GAA, which in turn can be used as a substrate by CK instead of PCr (Heerschap et al 2007). In contrast to the latter, mice with AGAT deficiency present with complete absence of creatine and GAA in all tissues of the body and, as would be expected, with a severe muscle phenotype associated with reduced muscle strength, muscle atrophy, decreased ATP and increased inorganic phosphate (Pi) levels (Nabuurs et al 2013). The latter situation results in significantly disturbed oxidative phosphorylation.…”

Section: Creatine and Cancermentioning

confidence: 99%

Creatine: a miserable life without it

Wallimann

Harris

2016

Amino Acids

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“…Mating, housing, and generation of mice were performed as described previously [18][19][20] (Methods in the online-only Data Supplement).…”

Section: Mouse Modelsmentioning

confidence: 99%

Homoarginine Levels Are Regulated by l -Arginine:Glycine Amidinotransferase and Affect Stroke Outcome

Choe¹,

Atzler²,

Wild³

et al. 2013

Circulation

135

164

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Background— Endogenous arginine homologues, including homoarginine, have been identified as novel biomarkers for cardiovascular disease and outcomes. Our studies of human cohorts and a confirmatory murine model associated the arginine homologue homoarginine and its metabolism with stroke pathology and outcome. Methods and Results— Increasing homoarginine levels were independently associated with a reduction in all-cause mortality in patients with ischemic stroke (7.4 years of follow-up; hazard ratio for 1-SD homoarginine, 0.79 [95% confidence interval, 0.64–0.96]; P =0.019; n=389). Homoarginine was also independently associated with the National Institutes of Health Stroke Scale+age score and 30-day mortality after ischemic stroke ( P <0.05; n=137). A genome-wide association study revealed that plasma homoarginine was strongly associated with single nucleotide polymorphisms in the l -arginine:glycine amidinotransferase ( AGAT ) gene ( P <2.1×10 −8 ; n=2806), and increased AGAT expression in a cell model was associated with increased homoarginine. Next, we used 2 genetic murine models to investigate the link between plasma homoarginine and outcome after experimental ischemic stroke: (1) an AGAT deletion (AGAT −/− ) and (2) a guanidinoacetate N -methyltransferase deletion (GAMT −/− ) causing AGAT upregulation. As suggested by the genome-wide association study, homoarginine was absent in AGAT −/− mice and increased in GAMT −/− mice. Cerebral damage and neurological deficits in experimental stroke were increased in AGAT −/− mice and attenuated by homoarginine supplementation, whereas infarct size in GAMT −/− mice was decreased compared with controls. Conclusions— Low homoarginine appears to be related to poor outcome after ischemic stroke. Further validation in future trials may lead to therapeutic adjustments of homoarginine metabolism that alleviate stroke and other vascular disorders.

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

Cited by 81 publications

References 107 publications

Creatine transporter deficiency leads to increased whole body and cellular metabolism

Creatine transporter deficiency leads to increased whole body and cellular metabolism

Creatine: a miserable life without it

Homoarginine Levels Are Regulated by l -Arginine:Glycine Amidinotransferase and Affect Stroke Outcome

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