Is creatine kinase responsible for fatigue? Studies of isolated skeletal muscle deficient in creatine kinase

Creatine kinase (CK) is a key enzyme for maintaining a constant ATP/ADP rat io during rapid energy turnover. To investigate the role of CK in skeletal muscle fatigue, we used isolated whole muscles and intact single fibers fro m CK-deficient mice (CK-/-). With high-intensity electrical stimulation, si ngle fibers from CK-/- mice displayed a transient decrease in both tetanic free myoplasmic [Ca2+] ([Ca2+](i) measured with the fluorescent dye indo-1) and force that was not observed in wild-type fibers. With less intense, re peated tetanic stimulation single fibers and EDL muscles, both of which are fast-twitch, fatigued more slowly in CK-/- than in wild-type mice; on the other hand, the slow-twitch soleus muscle fatigued more rapidly in CK-/- mi ce. In single wild-type fibers, tetanic force decreased and [Ca2+](i) incre ased during the first 10 fatiguing tetani, but this was not observed in CK- /- fibers. Fatigue was not accompanied by phosphocreatine breakdown and acc umulation of inorganic phosphate in CK-/- muscles. In conclusion, CK is imp ortant for avoiding fatigue at the onset of high-intensity stimulation, How ever, during more prolonged stimulation, CK may contribute to the fatigue p rocess by increasing the myoplasmic concentration of inorganic phosphate.