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Cytoarchitectural and metabolic adaptations in muscles with mitochondrial and cytosolic creatine kinase deficiencies

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Abstract

We have blocked creatine kinase (CK) mediated phosphocreatine (PCr) ⇄ ATP transphosphorylation in mitochondria and cytosol of skeletal muscle by knocking out the genes for the mitochondrial (ScCKmit) and the cytosolic (M-CK) CK isoforms in mice. Animals which carry single or double mutations, if kept and tested under standard laboratory conditions, have surprisingly mild changes in muscle physiology. Strenuous ex vivo conditions were necessary to reveal that MM-CK absence in single and double mutants leads to a partial loss of tetanic force output. Single ScCKmit deficiency has no noticeable effects but in combination the mutations cause slowing of the relaxation rate. Importantly, our studies revealed that there is metabolic and cytoarchitectural adaptation to CK defects in energy metabolism. The effects involve mutation type-dependent alterations in the levels of AMP, IMP, glycogen and phosphomonoesters, changes in activity of metabolic enzymes like AMP-deaminase, alterations in mitochondrial volume and contractile protein (MHC isoform) profiles, and a hyperproliferation of the terminal cysternae of the SR (in tubular aggregates). This suggests that there is a compensatory resiliency of loss-of-function and redirection of flux distributions in the metabolic network for cellular energy in our mutants.

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Authors and Affiliations

  1. Departments of Cell Biology and Histology, Faculty of Medical Sciences, University of Nijmegen, PO Box 9101, 6500 HB, Nijmegen, The Netherlands

    Karen Steeghs, Frank Oerlemans, Carolina Jost, Jan van Deursen, Paul Jap & Bé Wieringa

  2. Departments of Biochemistry, Faculty of Medical Sciences, University of Nijmegen, PO Box 9101, 6500 HB, Nijmegen, The Netherlands

    Ad Benders

  3. Institute for Fundamental and Clinical Human Movement Sciences, Faculty of Human Movement Sciences, Vrije University, Van der Boechorststraat 9, 1081 BT, Amsterdam, The Netherlands

    Arnold de Haan

  4. Department of Diagnostic Radiology, Faculty of Medical Sciences, University of Nijmegen, PO Box 9101, 6500 HB, Nijmegen, The Netherlands

    Arend Heerschap

  5. Center for Electronmicroscopy, University of Antwerp (UIA), Universiteitsplein 1, B-2610, Antwerpen, Belgium

    Lia Verdoodt, Martine de Bie & Wim Jacob

  6. Department of Physiology, State University of New York Health Science Center at Syracuse, Syracuse University, Syracuse, New York, 13210, USA

    Peter Tullson & Ronald Terjung

  7. Department of Paediatrics, Faculty of Medical Sciences, University of Nijmegen, PO Box 9101, 6500 HB, Nijmegen

    Wim Ruitenbeek

  8. Department of Biology, University of Konstanz, PO Box 5560/M641, Konstanz, D-7834, Germany

    Dirk Pette

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  1. Karen Steeghs
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  2. Frank Oerlemans
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  8. Ad Benders
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  9. Carolina Jost
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  10. Jan van Deursen
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Steeghs, K., Oerlemans, F., de Haan, A. et al. Cytoarchitectural and metabolic adaptations in muscles with mitochondrial and cytosolic creatine kinase deficiencies. Mol Cell Biochem 184, 183–194 (1998). https://doi.org/10.1023/A:1006811717709

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