Prolonged exercise to fatigue in humans impairs skeletal muscle Na⁺-K⁺-ATPase activity, sarcoplasmic reticulum Ca²⁺release, and Ca²⁺uptake

Abstract

Prolonged exhaustive submaximal exercise in humans induces marked metabolic changes, but little is known about effects on muscle Na+-K+-ATPase activity and sarcoplasmic reticulum Ca2+ regulation. We therefore investigated whether these processes were impaired during cycling exercise at 74.3 +/- 1.2% maximal O2 uptake (mean +/- SE) continued until fatigue in eight healthy subjects (maximal O2 uptake of 3.93 +/- 0.69 l/min). A vastus lateralis muscle biopsy was taken at rest, at 10 and 45 min of exercise, and at fatigue. Muscle was analyzed for in vitro Na+-K+-ATPase activity [maximal K+-stimulated 3-O-methylfluorescein phosphatase (3-O-MFPase) activity], Na+-K+-ATPase content ([3H]ouabain binding sites), sarcoplasmic reticulum Ca2+ release rate induced by 4 chloro-m-cresol, and Ca2+ uptake rate. Cycling time to fatigue was 72.18 +/- 6.46 min. Muscle 3-O-MFPase activity (nmol.min(-1).g protein(-1)) fell from rest by 6.6 +/- 2.1% at 10 min (P <0.05), by 10.7 +/- 2.3% at 45 min (P <0.01), and by 12.6 +/- 1.6% at fatigue (P <0.01), whereas 3[H]ouabain binding site content was unchanged. Ca2+ release (mmol.min(-1).g protein(-1)) declined from rest by 10.0 +/- 3.8% at 45 min (P <0.05) and by 17.9 +/- 4.1% at fatigue (P < 0.01), whereas Ca2+ uptake rate fell from rest by 23.8 +/- 12.2% at fatigue (P=0.05). However, the decline in muscle 3-O-MFPase activity, Ca2+ uptake, and Ca2+ release were variable and not significantly correlated with time to fatigue. Thus prolonged exhaustive exercise impaired each of the maximal in vitro Na+-K+-ATPase activity, Ca2+ release, and Ca2+ uptake rates. This suggests that acutely downregulated muscle Na+, K+, and Ca2+ transport processes may be important factors in fatigue during prolonged exercise in humans.

Skeletal Muscle Fatigue: Cellular Mechanisms

“…A number of studies have reported that Ca 2ϩ release from isolated SR is reduced by ϳ20 -40% following prolonged or intense exercise in humans (210,284,285) and rodents (161), although some studies found no change (111,396) or a reduction in slow-twitch but not fast-twitch muscle (161,221). It is unclear how long this effect persists after exercise, as this was only examined in one study to date, and the results were somewhat equivocal at the one recovery time examined (3.5 h) (210 ] i also greatly prolongs PCD in Xenopus fast-twitch fibers (69,70,269).…”

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

“…Muscle fatigue is a very complex phenomenon that involves multiple cellular correlates, e.g., transmission failure of action potentials, tubular excitation spread failure, voltage sensor dysregulation, SR Ca 2ϩ release, metabolic impairment through ATP depletion or reuptake alterations, or myofibrillar protein alterations (13,28,172,417,572,657). In critically ill patients, muscle fatigue is usually only assessed via nerval routes either using voluntary muscle exercise (278) or nerve stimulation (181).…”

Impaired calcium release during fatigue

“…Finally, and perhaps of greatest importance, the Ca 2ϩ release channel is also strongly inhibited by cytoplasmic Mg 2ϩ (80) (37), although it is apparent that they are not the only metabolic factors involved in reducing Ca 2ϩ release in fatigue (38). A number of studies have reported that Ca 2ϩ release from isolated SR is reduced up to ϳ40% following prolonged or intense exercise in humans (63,83,84). However, in such studies the Ca 2ϩ release was triggered by non-physiological means, such as by caffeine, chloro-m-cresol, or the oxidizing agent Ag ϩ , and the rate of release was more than 30 times slower than occurs when activating Ca 2ϩ release by the normal voltage sensor mechanism.…”