CYTOARCHITECTURAL AND METABOLIC ADAPTATIONS IN MUSCLES WITH MITOCHONDRIAL AND CYTOSOLIC CREATINE-KINASE DEFICIENCIES

We have blocked creatine kinase (CK) mediated phosphocreatine (PCr) re versible arrow ATP transphosphorylation in mitochondria and cytosol of skeletal muscle by knocking out the genes for the mitochondrial (ScCK mit) and the cytosolic (M-CK) CK isoforms in mice. Animals which carry single or double mutations, if kept and tested under standard laborat ory conditions, have surprisingly mild changes in muscle physiology. S trenuous ex vivo conditions were necessary to reveal that MM-CK absenc e in single and double mutants leads to a partial loss of tetanic forc e output. Single ScCKmit deficiency has no noticeable effects but in c ombination the mutations cause slowing of the relaxation rate. Importa ntly, our studies revealed that there is metabolic and cytoarchitectur al adaptation to CK defects in energy metabolism. The effects involve mutation type-dependent alterations in the levels of AMP, IMP, glycoge n and phosphomonoesters, changes in activity of metabolic enzymes like AMP-deaminase, alterations in mitochondrial volume and contractile pr otein (MHC isoform) profiles, and a hyperproliferation of the terminal cysternae of the SR tin tubular aggregates). This suggests that there is a compensatory resiliency of loss-of-function and redirection of f lux distributions in the metabolic network for cellular energy in our mutants.