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Activation of Ca2+-dependent protein kinase II during repeated contractions in single muscle fibres from mouse is dependent on the frequency of sarcoplasmic reticulum Ca2+ release

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Abstract Aim: 

To investigate the importance and contribution of calmodulin-dependent protein kinase II (CaMKII) activity on sarcoplasmic reticulum (SR) Ca2+-release in response to different work intensities in single, intact muscle fibres. Methods: 

CaMKII activity was blocked in single muscle fibres using either the inhibitory peptide AC3-I or the pharmacological inhibitor KN-93. The effect on tetanic force production and [Ca2+]i was determined during work of different intensities. The activity of CaMKII was assessed by mathematical modelling. Results: 

Using a standard protocol to induce fatigue (50× 70 Hz, 350 ms duration, every 2 s) the number of stimuli needed to induce fatigue was decreased from 47 ± 3 contractions in control to 33 ± 3 with AC3-I. KN-93 was a more potent inhibitor, decreasing the number of contractions needed to induce fatigue to 15 ± 3. Tetanic [Ca2+]i was 100 ± 11%, 97 ± 11% and 67 ± 11% at the end of stimulation in control, AC3-I and KN-93 respectively. A similar inhibition was obtained using a high intensity protocol (20× 70 Hz, 200 ms duration, every 300 ms). However, using a long interval protocol (25× 70 Hz, 350 ms duration, every 5 s) no change was observed in either tetanic [Ca2+]i or force when inhibiting CaMKII. A mathematical model used to investigate the activation pattern of CaMKII suggests that there is a threshold of active CaMKII that has to be surpassed in order for CaMKII to affect SR Ca2+ release. Conclusion: 

Our results show that CaMKII is crucial for maintaining proper SR Ca2+ release and that this is regulated in a work intensity manner.
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Keywords: AC3-I; Ca2+; CaMKII; KN-93; fatigue; sarcoplasmic reticulum; skeletal muscle

Document Type: Research Article

Affiliations: 1:  Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden 2:  Department of Physiology and Biocenter Oulu, University of Oulu, Oulu, Finland 3:  Bosch Institute and School of Medical Sciences, University of Sydney, Sydney, NSW, Australia

Publication date: 2007-10-01

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