Intracellular mechanisms of skeletal muscle fatigue : role of creatine kinase

Abstract

During intense physical activity the maximal power output of skeletal muscles is reduced, a condition described as muscle fatigue. The cause of impaired muscle function seen in fatigue is multifactorial. Creatine kinase (CK, catalyzes PCr + ADP 4n Cr + ATP) is considered important for niinimizing changes of [ATP]/[ADP] that may occur during periods of intense activity. Using knockout mice that lack the gene coding for CK (CC mice) andlor by inhibiting CK pharmacologically, the role of CK was studied during skeletal muscle fatigue, both in whole muscles and single intact muscle fibres.

The maximum shortening velocity (Vo) was reduced during fatigue or with inhibition of CK with 2,4-dinitro-l-fluorobenzene (DNFB). These results are consistent with the idea that an increased ADP reduces Vo during fatigue. Furthermore, both CK-/- and DNFB exposed fibres displayed a transient decline of [Ca2+]i and force early in fatiguing stimulation. This shows that PCr breakdown supports SR Ca2+ release during short term, high-intensity activity. However, during low-intensity fatiguing stimulation, tetanic [Ca2+]i and force are better maintained in fibres with nonoperating CK as compared to control fibres. This indicates that PCr breakdown may actually cause failure of SR Ca2+ release and contribute to fatigue during low-intensity stimulation. To distinguish between possible adaptive changes and direct CK effects in single CC muscle fibres, contractile performance was compared at rest and during high-intensity fatiguing stimulation before and after injection of purified CK.

The results show that the wild-type phenotype is partially restored in CKinjected CK-/- fibres. Fast-twitch muscles of Ck-/--mice provides a good model for. studying the effects of Pi on muscle function, since they have higher Pi at rest and do not accumulate Pi during fatigue. Using this model, all major functional changes observed in early fatigue can be explained by an increased [Pi]; that is, Pi reduces tetanic force and myofibrillar Ca2+ sensitivity, increases tetanic [Ca2+]i, slows force relaxation, and reduces the rate of SR Ca2+ uptake. In conclusion, increased [ADP] and [Pi] are important factors in skeletal muscle fatigue.