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


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.

DOI: 10.1023/A:1006811717709

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@article{Steeghs1998CytoarchitecturalAM, title={Cytoarchitectural and metabolic adaptations in muscles with mitochondrial and cytosolic creatine kinase deficiencies}, author={Karen Steeghs and Frank T . J . J . Oerlemans and Arnold de Haan and Arend Heerschap and Lia Verdoodt and Martine de Bie and Wim Ruitenbeek and A . G . M . Benders and Carolina Jost and Jan M . van Deursen and Peter Tullson and Ronald Terjung and Paul H. K. Jap and Wim A. Jacob and Dirk Pette and B. Wieringa}, journal={Molecular and Cellular Biochemistry}, year={1998}, volume={184}, pages={183-194} }