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Contractile dysfunctions in ATP‐dependent K + channel‐deficient mouse muscle during fatigue involve excessive depolarization and Ca 2+ influx through L‐type Ca 2+ channels
Author(s) -
Cifelli Carlo,
Boudreault Louise,
Gong Bing,
Bercier JeanPhilippe,
Renaud JeanMarc
Publication year - 2008
Publication title -
experimental physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.925
H-Index - 101
eISSN - 1469-445X
pISSN - 0958-0670
DOI - 10.1113/expphysiol.2008.042572
Subject(s) - depolarization , verapamil , chemistry , contraction (grammar) , medicine , endocrinology , membrane potential , extracellular , channel blocker , muscle contraction , biophysics , muscle fatigue , calcium , biochemistry , biology , neuroscience , electromyography
Muscles deficient in ATP‐dependent potassium (K ATP ) channels develop contractile dysfunctions during fatigue that may explain their apparently faster rate of fatigue compared with wild‐type muscles. The objectives of this study were to determine: (1) whether the contractile dysfunctions, namely unstimulated force and depressed force recovery, result from excessive membrane depolarization and Ca 2+ influx through L‐type Ca 2+ channels; and (2) whether reducing the magnitude of these two contractile dysfunctions reduces the rate of fatigue in K ATP channel‐deficient muscles. To reduce Ca 2+ influx, we lowered the extracellular Ca 2+ concentration ([Ca 2+ ] o ) from 2.4 to 0.6 m m or added 1 μ m verapamil, an L‐type Ca 2+ channel blocker. Flexor digitorum brevis (FDB) muscles deficient in K ATP channels were obtained by exposing wild‐type muscles to 10 μ m glibenclamide or by using FDB from Kir6.2 −/− mice. Fatigue was elicited with one contraction per second for 3 min at 37°C. In wild‐type FDB, lowered [Ca 2+ ] o or verapamil did not affect the decrease in peak tetanic force and unstimulated force during fatigue and force recovery following fatigue. In K ATP channel‐deficient FDB, lowered [Ca 2+ ] o or verapamil slowed down the decrease in peak tetanic force recovery, reduced unstimulated force and improved force recovery. In Kir6.2 −/− FDB, the rate of fatigue became slower than in wild‐type FDB in the presence of verapamil. The cell membrane depolarized from −83 to −57 mV in normal wild‐type FDB. The depolarizations in some glibenclamide‐exposed fibres were similar to those of normal FDB, while in other fibres the cell membrane depolarized to −31 mV in 80 s, which was also the time when these fibres supercontracted. It is concluded that: (1) K ATP channels are crucial in preventing excessive membrane depolarization and Ca 2+ influx through L‐type Ca 2+ channels; and (2) they contribute to the decrease in force during fatigue.