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Creatine transporter deficiency leads to increased whole body and cellular metabolism

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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.

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Acknowledgments

This work was supported by the National Institutes of Health grants HD080910 (MRS), TR000077 (MRS), and ES07051 (KNM).

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Authors and Affiliations

  1. Division of Neurology, Cincinnati Children’s Research Foundation, 3333 Burnet Ave, ML 7044, Cincinnati, OH, 45229, USA

    Marla K. Perna, Amanda N. Kokenge, Keila N. Miles, Kenea C. Udobi & Matthew R. Skelton

  2. Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, USA

    Joseph F. Clark

  3. Department of Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, USA

    Gail J. Pyne-Geithman

  4. Heart Institute, Cincinnati Children’s Research Foundation, Cincinnati, USA

    Zaza Khuchua

  5. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, USA

    Marla K. Perna, Amanda N. Kokenge, Keila N. Miles, Kenea C. Udobi, Zaza Khuchua & Matthew R. Skelton

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  1. Marla K. Perna
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  2. Amanda N. Kokenge
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  8. Matthew R. Skelton
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Correspondence to Matthew R. Skelton.

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Ethical statement

All procedures involving animals have been approved by the Cincinnati Children’s Research Foundation Institutional Animal Care and Use Committee (CCRF IACUC), which is fully accredited by the International Association for Assessment and Accreditation of Laboratory Animal Care.

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The authors declare no conflict of interest.

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Handling Editor: T. Wallimann and R. Harris.

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Perna, M.K., Kokenge, A.N., Miles, K.N. et al. Creatine transporter deficiency leads to increased whole body and cellular metabolism. Amino Acids 48, 2057–2065 (2016). https://doi.org/10.1007/s00726-016-2291-3

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  • DOI: https://doi.org/10.1007/s00726-016-2291-3

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