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Inhibition of creatine kinase reduces the rate of fatigue-induced decrease in tetanic [Ca²⁺]_i in mouse skeletal muscle

Anders J. Dahlstedt and Håkan Westerblad

1. Ca²⁺-phosphate (P_i) precipitation in the sarcoplasmic reticulum (SR) may cause reduced SR Ca²⁺ release in skeletal muscle fatigue. To study this, we inhibited the creatine kinase (CK) reaction with 2,4-dinitro-1-fluorobenzene (DNFB). The hypothesis was that with inhibition of CK, phosphocreatine would not break down to creatine and P_i. Therefore P_i transport into the SR would be limited and Ca²⁺-P_i precipitation would not occur.
2. Intact single fibres from a mouse foot muscle were fatigued by repeated short tetani under control conditions or after exposure to DNFB (10 µM). The free myoplasmic concentrations of Ca²⁺ ([Ca²⁺]_i) and Mg²⁺ ([Mg²⁺]_i) were measured with indo-1 and mag-indo-1, respectively. Changes in [Mg²⁺]_i were assumed to reflect alterations in myoplasmic ATP concentration.
3. During the first 10 fatiguing tetani, tetanic [Ca²⁺]_i increased both in control and after DNFB exposure. Thereafter tetanic [Ca²⁺]_i fell and the rate of fall was about fourfold lower after DNFB exposure compared with control.
4. Under control conditions, there was a good relationship between declining tetanic [Ca²⁺]_i and increasing [Mg²⁺]_i during the final part of fatiguing stimulation. This correlation was lost after DNFB exposure.
5. In conclusion, the present data fit with a model where Ca²⁺-P_i precipitation inhibits SR Ca²⁺ release in fatigue produced by repeated short tetani. Furthermore, the results suggest that the rate of P_i transport into the SR critically depends on the myoplasmic Mg²⁺/ATP concentration.

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