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Muscle creatine kinase-deficient mice. I. Alterations in myofibrillar function
R Ventura-Clapier1, A V Kuznetsov, A d'Albis
1Laboratoire de Cardiologie Cellulaire et Moléculaire, CJF INSERM 92-11, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France.
The Journal of Biological Chemistry
|August 25, 1995
Summary
Mice lacking the M-isoform of creatine kinase gene showed no changes in muscle force or calcium sensitivity. However, altered bioenergetic pathways, including glycolysis, impacted contractile regulation in these transgenic mice.
Area of Science:
- Muscle physiology
- Bioenergetics
- Biochemistry
Background:
- Creatine kinase (CK) plays a vital role in cellular energy buffering.
- The M-isoform of CK is predominantly found in skeletal and cardiac muscle.
- Understanding its role is crucial for muscle function and energy metabolism.
Purpose of the Study:
- To investigate the regulation of contractile activity in mice with a null mutation of the M-isoform of creatine kinase gene.
- To explore the impact of this mutation on muscle bioenergetics and myofibrillar function.
- To identify adaptations in metabolic pathways in response to the genetic modification.
Main Methods:
- Analysis of tissue extracts and Triton X-100-treated muscle preparations (ventricular, soleus, gastrocnemius) from control and transgenic mice.
- Skinned fiber experiments to assess maximal force, calcium sensitivity, and rigor tension development.
- Measurement of enzyme activities (myokinase, pyruvate kinase, glyceraldehyde-3-phosphate dehydrogenase).
Main Results:
- No significant differences in maximal force or calcium sensitivity were observed between control and transgenic mice.
- Rigor tension development was influenced by phosphocreatine in control but not transgenic mice.
- Ventricular preparations showed slowed tension changes in transgenic mice, suggesting hindered cross-bridge cycling due to a decreased MgATP/MgADP ratio.
- Increased activities of pyruvate kinase and glyceraldehyde-3-phosphate dehydrogenase were noted in transgenic animals, indicating adaptations in glycolytic metabolism.
Conclusions:
- The absence of the M-isoform of creatine kinase does not fundamentally alter myofibrillar structure.
- Significant adaptations occur in bioenergetic pathways, including enhanced glycolytic metabolism, to compensate for the lack of phosphocreatine buffering.
- These adaptations modify muscle contractile regulation by impacting local ATP/ADP ratios and cross-bridge cycling efficiency.