Abstract
Fatigue of single mouse fibers during repeated high-frequency stimulation results initially from decreased Ca2+ sensitivity while free myoplasmic calcium concentration ([Ca2+]m) increases, followed by decreasing [Ca2+]m. Recovery of active force with low-frequency stimulation is slow and persistent fatigue results from low [Ca2+]m. However, the consequences of intermittent submaximal contractions are not known. The aim of the present study was to investigate the changes in [Ca2+]m and active force during intermittent submaximal contractions and subsequent recovery. Single fibers of mouse flexor digitorum brevis muscles at 32 °C were stimulated with 40 or 50 Hz, for 350 ms every 2 s for 2 min and then every 1 s until < 40% of initial force. Values obtained during the intermittent stimulation were compared with a control force-[Ca2+]m relationship. A “P”-shaped pattern in the force-[Ca2+]m relationship was observed during intermittent stimulation. Early in the intermittent stimulation, [Ca2+]m increased while active force decreased. Subsequent force potentiation was accompanied by increased Ca2+ sensitivity. Later, as active force declined, [Ca2+]m decreased significantly (p < 0.001). This was followed, in the final phase, by a significant decrease in Ca2+ sensitivity determined by [Ca2+]m at half-maximal force (Ca50) (p = 0.001). Low-frequency fatigue persisted during recovery while Ca50 was not significantly different from prefatigue (p > 0.5). In conclusion, the main mechanism of fatigue is due to decreases in both [Ca2+]m and Ca2+ sensitivity following the initial force potentiation. The intermittent submaximal contractions resulted in persistent low-frequency fatigue seen during recovery, which was explained by depressed [Ca2+]m with no change in Ca2+ sensitivity.
Highlights
The force exerted by a muscle expressed relative to myoplasmic free Ca2+ concentration ([Ca2+]m) gives a sigmoidal relationship [1, 2]
During the time course of intermittent stimulation, expressed as percent of total time, an initial decrease in active force was observed, followed by an increase in active force until about 30% into the duration
It can be seen here that these Brecovery^ contractions progressively decreased in amplitude, at the low frequencies. These control tests were completed to evaluate the impact of collecting these contractions on our assessment of recovery. These results indicate that the recovery contractions would have slowed the actual recovery following the intermittent contractions
Summary
The force exerted by a muscle expressed relative to myoplasmic free Ca2+ concentration ([Ca2+]m) gives a sigmoidal relationship [1, 2]. Observations of contractions under different conditions (frequency of stimulation, activitydependent potentiation, force depression due to prior sensitivity can be represented by a change in half-maximal [Ca2+] (Ca50), where a shift of the curve to higher [Ca2+]m represents a decrease in Ca2+ sensitivity [1]. We know that the [Ca2+]m is dependent on the frequency of activation [7] and that during intermittent stimulation at a fixed high-frequency, there is initially an increase in [Ca2+]m in the early stages and a decrease in the late stages of fatigue [8]. Force decreases when [Ca2+]m increases in the early stages, followed by a simultaneous decrease in both force and [Ca2+]m in the late stages of fatigue. The pattern of change in [Ca2+]m is Pflugers Arch - Eur J Physiol (2018) 470:1243–1254 not known for intermittent low-frequency stimulation in mammalian muscles, a situation that is more compatible with in vivo muscle activation
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