KATP channel deficiency in mouse flexor digitorum brevis causes fibre damage and impairs Ca2+ release and force development during fatigue in vitro

Carlo Cifelli, François Bourassa, Louise Gariépy, Krystyna Banas, Maria Benkhalti, Jean-Marc Renaud
Journal of Physiology 2007 July 15, 582 (Pt 2): 843-57
Activation of the K(ATP) channels results in faster fatigue rates as the channels depress action potential amplitude, whereas abolishing the channel activity has no effect in whole extensor digitorum longus (EDL) and soleus muscles. In this study, we examined the effects of abolished K(ATP) channel activity during fatigue at 37 degrees C on free intracellular Ca(2+) (Ca(2+)(i)) and tetanic force using single muscle fibres and small muscle bundles from the flexor digitorum brevis (FDB). K(ATP) channel deficient muscle fibres were obtained (i) pharmacologically by exposing wild-type fibres to glibenclamide, and (ii) genetically using null mice for the Kir6.2 gene (Kir6.2(-/-) mice). Fatigue was elicited using 200 ms tetanic contractions every second for 3 min. This study demonstrated for the first time that abolishing K(ATP) channel activity at 37 degrees C resulted in faster fatigue rates, where decreases in peak Ca(2+)(i) and tetanic force were faster in K(ATP) channel deficient fibres than in control wild-type fibres. Furthermore, several contractile dysfunctions were also observed in K(ATP) channel deficient muscle fibre. They included partially or completely supercontracted single muscle fibres, greater increases in unstimulated Ca(2+)(i) and unstimulated force, and lower force recovery. We propose that the observed faster rate of fatigue in K(ATP) channel deficient fibres is because the decreases in peak Ca(2+)(i) and force caused by contractile dysfunctions prevail over the expected slower decreases when the channels do not depress action potential amplitude.

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