Altered Ca²⁺ responses in muscles with combined mitochondrial and cytosolic creatine kinase deficiencies

We have blocked creatine kinase (CK)-mediated phosphocreatine (PCr) ⇆ ATP transphosphorylation in skeletal muscle by combining targeted mutations in the genes encoding mitochondrial and cytosolic CK in mice. Contrary to expectation, the PCr level was only marginally affected, but the compound was rendered metabolically inert. Mutant muscles in vivo showed significantly impaired tetanic force output, increased relaxation times, altered mitochondrial volume and location, and conspicuous tubular aggregates of sarcoplasmic reticulum membranes, as seen in myopsthies with electrolyte disturbances. In depolarized myotubes cultured in vitro, CK absence influenced both the release and sequestration of Ca²⁺. Our data point to a direct link between the CK-PCr system and Ca²⁺flux regulation during the excitation and relaxation phases of muscle contraction.