Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Aug;48(8):2057-65.
doi: 10.1007/s00726-016-2291-3. Epub 2016 Jul 11.

Creatine transporter deficiency leads to increased whole body and cellular metabolism

Marla K Perna  1   2 , Amanda N Kokenge  1   2 , Keila N Miles  1   2 , Kenea C Udobi  1   2 , Joseph F Clark  3 , Gail J Pyne-Geithman  4 , Zaza Khuchua  5   2 , Matthew R Skelton  6   7
Affiliations

Creatine transporter deficiency leads to increased whole body and cellular metabolism

Marla K Perna et al. Amino Acids. 2016 Aug.

Abstract

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 a significant intellectual impairment, epilepsy, and aphasia. The lack of Cr on both the 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 and, however, show a twofold increase in body fat. There was increased energy expenditure in a home cage environment and during treadmill running in Crt (-/y) mice. Consistent with the increases in the whole-body metabolic function, Crt (-/y) mice show increased 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. 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.

Keywords: Creatine; Creatine transporter; Creatine transporter deficiency; Mitochondria.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest: The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Crt−/y mice show reductions in body weight (A) and food intake (C) compared with Crt+/y mice. Interestingly, Crt−/y mice had a higher body fat percentage (B) compared with Crt+/y mice. (D) Shows a representative image of Crt+/y (left) and Crt−/y (right) mice. Values are mean +/− SEM. *p<0.05 n=6–13 per group
Figure 2
Figure 2
Crt−/y mice have reduced ATP levels in the brain, heart and muscle compared with Crt+/y mice. Values are mean +/− SEM. *p<0.05 n=6 per group
Figure 3
Figure 3
Crt−/y mice show increased calorie use, oxygen consumption and carbon dioxide release compared with Crt+/y mice. Line above x-axis denotes dark cycle of testing. n=8–10 per group Values are mean +/− SEM.
Figure 4
Figure 4
Crt−/y mice show increased calorie use, oxygen consumption and carbon dioxide release compared with Crt+/y mice when exercising on a treadmill. As time progressed, speed was increased. The increase in gas exchange observed at ~15 min likely reflects a switch to alternate fuel sources. *p<0.05 n=4–6 per group. Values are mean +/− SEM.
Figure 5
Figure 5
Crt−/y mice show increased mitochondrial respiration (A) and respiratory control ratio (B) in hippocampal lysates. (C) Stimulated respiration was increased in permeabilized muscle fibers from Crt−/y mice. (D) Increased citrate synthase activity in samples tested for respirometry is observed in Crt−/y mice. *p<0.05 n=6 per group. Values are mean +/− SEM.
Figure 6
Figure 6
Isolated mitochondria from the hippocampus of Cr+/y and Crt−/y mice show similar oxygen consumption when equal numbers of mitochondria are examined. (A) Oxygen consumption was examined in isolated mitochondria the presence of malate and pyruvate. No differences were observed between groups. (B) Complex II activity was assessed by incubating mitochondria with rotenone and succinate prior to respirometry. Values are mean +/− SEM, n=4 with each sample run in duplicate.
Figure 7
Figure 7
In isolated mitochondria from the hippocampus, no differences were observed in ETC CI through CV protein levels. Data were normalized to β-Actin and expressed as a % of Crt+/y control. *p<0.05 n=4 per group
See this image and copyright information in PMC

References

    1. Alcaide P, Merinero B, Ruiz-Sala P, Richard E, Navarrete R, Arias A, Ribes A, Artuch R, Campistol J, Ugarte M, Rodriguez-Pombo P. Defining the pathogenicity of creatine deficiency syndrome. Human mutation. 2011;32(3):282–291. - PubMed
    1. Braissant O, Henry H, Beard E, Uldry J. Creatine deficiency syndromes and the importance of creatine synthesis in the brain. Amino Acids. 2011 - PubMed
    1. Clark AJ, Rosenberg EH, Almeida LS, Wood TC, Jakobs C, Stevenson RE, Schwartz CE, Salomons GS. X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology. Hum Genet. 2006;119(6):604–610. - PubMed
    1. Cunha MP, Budni J, Ludka FK, Pazini FL, Rosa JM, Oliveira A, Lopes MW, Tasca CI, Leal RB, Rodrigues AL. Involvement of PI3K/Akt Signaling Pathway and Its Downstream Intracellular Targets in the Antidepressant-Like Effect of Creatine. Mol Neurobiol. 2015 - PubMed
    1. deGrauw TJ, Cecil KM, Byars AW, Salomons GS, Ball WS, Jakobs C. The clinical syndrome of creatine transporter deficiency. Molecular and cellular biochemistry. 2003;244(1–2):45–48. - PubMed

Publication types

Substances

LinkOut - more resources