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Mice deficient in ubiquitous mitochondrial creatine kinase are viable and fertile

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Changes in glycolytic network and mitochondrial design in creatine kinase-deficient muscles.

Skeletal muscles respond with high plasticity to pathobiological conditions or changes in physiological demand by remodeling cytoarchitectural and metabolic characteristics of individual myocytes. We have previously shown that muscles of mice without mitochondrial and/or cytosolic creatine kinases (ScCKmit(-/-) and/or M-CK(-/-)) partly compensate for the defect(s) by redirecting metabolic pathways and ultrastructural characteristics. Here, we show by semiquantitative Western blot analysis that the compensatory changes involve mutation- and fiber-type-specific coordinated regulation of divergent but functionally coupled groups of proteins. Fast-twitch gastrocnemius muscle of CK(--/--) mice display a two- to fourfold upregulation of mitochondrial cytochrome c oxidase, inorganic phosphate carrier, adenine nucleotide translocator, and voltage-dependent anion channel proteins. In parallel, cytosolic myoglobin is upregulated. Slow-twitch soleus muscle responds with changes in the glycolytic enzyme pattern, including a shift in lactate dehydrogenase isoenzyme composition. Adaptations in the network for oxidative adenosine triphosphate (ATP) production are already apparent at 17 days of age

Effects of ischemia on skeletal muscle energy metabolism in mice lacking creatine kinase monitored by in vivo P-31 nuclear magnetic resonance spectroscopy

The aim of this study was to provide in vivo experimental evidence for the proposed biological significance of the creatine kinase (CK)/phosphocreatine (PCr) system in the energy metabolism of skeletal muscle. As a test system we compared hindlimb muscle of knockout mice lacking the cytosolic M-type (M-CK(-)/(-)), the mitochondrial ScMit-type (ScCKmit(-)/(-)), or both creatine kinase isoenzymes (CK(-)/(-)), and in vivo 31P-NMR was used to monitor metabolic responses during and after an ischemic period. Although single mutants show some subtle specific abnormalities, in general their metabolic responses appear similar to wild type, in contrast to CK(-)/(-) double mutants. This implies that presence of one CK isoform is both necessary and sufficient for the system to be functional in meeting ischemic stress conditions. The global ATP buffering role of the CK/PCr system became apparent in a 30% decline of ATP in the CK(-)/(-) mice during ischemia. Both M-CK(-)/(-) and CK(-)/(-) showed increased phosphomonoester levels during ischemia, most likely reflecting adaptation to a more efficient utilization of glycogenolysis. While in M-CK(-)/(-) muscle PCr can still be hydrolyzed to provide Pi for this process, in CK(-)/(-) muscle only Pi from ATP breakdown is available and Pi levels increase much more slowly. The experiments also revealed that the system plays a role in maintaining pH levels; the CK(-)/(-) mice showed a faster and more pronounced acidification (pH = 6.6) than muscles of wild type and single knockout mutants (pH = 6.9)

Short TE CSI at 7 T of the mouse brain

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Glycolytic Metabolism is Differentially Coupled to Proliferative Potential and Morphodynamic Capacity in RAW 264.7 and Mafb/C-Maf Deficient Macrophage Lineages

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Structural and behavioural consequences of double deficiency for creatine kinases BCK and UbCKmit.

Contains fulltext : 48146.pdf (publisher's version ) (Closed access)The cytosolic brain-type creatine kinase (BCK) isoform and the mitochondrial ubiquitous creatine kinase (UbCKmit) isoform are both important for the maintenance and distribution of cellular energy in neurons and astrocytes. Previously, we reported that mice deficient for BCK or UbCKmit each showed a surprisingly mild phenotype, probably due to reciprocal functional compensation by the remaining creatine kinase. This study shows that adult male mice lacking both creatine kinase isoforms (CK--/-- double knockout mice) have a reduced body weight, and demonstrate a severely impaired spatial learning in both a dry and a wet maze, lower nestbuilding activity and diminished acoustic startle reflex responses when compared to age-matched male wildtype mice with the same genetic background. In contrast, their visual and motor functions, exploration behaviour, prepulse inhibition and anxiety-related responses were not changed, suggesting no global deficit in sensorimotor function, hearing or motivation. Morphological analysis of CK--/-- double knockout brains revealed a reduction of approximately 7% in wet brain weight and hippocampal size, a approximately 15% smaller regio-inferior and relatively larger supra-pyramidal, and intra-infra-pyramidal mossy fiber areas. These results suggest that lack of both brain specific creatine kinase isoforms renders the synaptic circuitry in adult brain less efficient in coping with sensory or cognitive activity related challenges

Proton MR spectroscopy of Wild-Type and creatine kinase deficient mouse skeletal muscle: dipole-dipole coupling effects and post-mortem changes

Localized proton MR spectra of mouse skeletal muscle obtained at 7 T show dipole-dipole coupling effects for creatine and putative taurine resonances and for the lactate methine signal. These effects are independent of the presence of creatine kinase. The intensity of the methylene (1)H resonance of creatine is not different between wild-type and creatine kinase deficient mice, which have a lower phosphocreatine content. (1)H-MR spectra acquired post-mortem from wild-type mouse skeletal muscle parallel to B(0) show a linewidth decrease for the methyl resonance of creatine and a 20% signal intensity loss for its methylene peak concurrent with the total breakdown of phosphocreatine as observed by (31)P-MR spectroscopy. However, with the muscle at the magic angle no changes in the appearance and intensity of creatine (and taurine) resonances are observed. These results indicate that the changes observed for creatine resonances are related to altered dipolar couplings and that the intensity of the methylene peak does not necessarily reflect muscular phosphocreatine content