Ion Movements in Skeletal Muscle in Relation to the Activation of Contraction

Events of the excitation–contraction–relaxation (E–C–R) cycle in fast‐ and slow‐twitch mammalian muscle fibres relevant to muscle fatigue

“…Theoretical considerations (Stephenson 1996) indicate that the kinetics of Mg 2+ dissociation from the modified inhibitory site is consistent with the rapid onset of Ca 2+ release following depolarization of the T‐tubules and also that the kinetics of Mg 2+ (1 m M ) binding to the inhibitory site is consistent with the rapid closure of the SR Ca 2+ release channels upon deactivation of the voltage sensors. This proposal extends the earlier model put forward by Ashley & Moisescu (1973) (see also Lüttgau & Moisescu 1978, Lüttgau & Stephenson 1986, Ashley et al 1991) where the rate of Ca 2+ release was assumed to be a function of both myoplasmic [Ca 2+ ] and surface membrane depolarization, and readily explains all findings to date. It is important to emphasize here that if the result of signal transmission from the voltage sensors in the T‐tubules to the RyR/Ca 2+ release channels in the SR is a decrease in the affinity for [Mg 2+ ] to the inhibitory site by a certain factor, then, a rise in [Mg 2+ ] above 1 m M or a decrease in [ATP] in the vicinity of the RyR/Ca 2+ release channels below m M concentrations would result in fewer RyR/Ca 2+ release channels opening.…”

“…Recent experiments with fast Ca 2+ ‐sensitive fluorescent dyes demonstrated that in the frog (Claflin et al 1994a) and fast‐twitch mammalian skeletal muscle fibres (Bakker et al 1997), the peak of the myoplasmic [Ca 2+ ] transient occurs before positive tension generation in the fibre (which is significantly earlier than previously thought) and that the rate at which the myoplasmic [Ca 2+ ] decreases during rapid force generation is very rapid compared with the time course of the force response. Another important observation was that the SR Ca 2+ pump turns on with a delay following the rapid rise in myoplasmic [Ca 2+ ] (Claflin et al 1994b), as earlier predicted by us (Ashley & Moisescu 1973, Ashley et al 1974, Lüttgau & Moisescu 1978, Lüttgau & Stephenson 1986). The relatively slow onset of the SR Ca 2+ pump could be related to relatively slow kinetics of Ca 2+ binding to the pump sites, phosphorylation of the pump sites and/or redistribution of the Ca 2+ binding pump sites across the SR membrane.…”

“…As mentioned above, the rapid decline of the myoplasmic [Ca 2+ ] transient (Claflin et al 1994a) following the rapid release of Ca 2+ from the terminal cisternae of the sarcoplasmic reticulum appears to be caused in the first instance by the numerous Ca 2+ binding sites in the myoplasm (see review by Lüttgau & Stephenson 1986) which bind Ca 2+ when the [Ca 2+ ] in their immediate vicinity is higher than at rest (Claflin et al 1994a). Nevertheless, for the myoplasmic [Ca 2+ ] to return to the resting level, and for the muscle fibre to relax fully, all released Ca 2+ must be resequestered by the SR.…”

“…The release of Ca 2+ from the SR causes a rise of [Ca 2+ ] in the myoplasm and it is important to appreciate that the magnitude and the time course of this intracellular [Ca 2+ ] rise are determined by the interplay between various Ca 2+ fluxes associated with the SR (SR Ca 2+ release, SR Ca 2+ uptake, Ca 2+ fluxes associated with the SR Ca 2+ binding sites on the SR Ca 2+ pump and RyR/Ca 2+ release channels) and the reversible Ca 2+ binding to several categories of sites present in the myoplasm (Ca 2+ regulatory sites on myofilaments, Ca 2+ binding sites on soluble Ca 2+ binding proteins such as parvalbumin and calmodulin and on small molecules such as ATP and P i ) (Ashley & Moisescu 1973, Lüttgau & Moisescu 1978, Lüttgau & Stephenson 1986, Melzer et al 1987). When all these factors are taken into account, it can be shown that the rise of the [Ca 2+ ] in the myoplasm represents only a very small fraction (about 1%) of the total Ca released from the SR.…”

“…1) does not develop force because of the inhibitory action exerted by the Ca 2+ regulatory system which permits only weak or no interactions between myosin cross‐bridges and actin filaments. When the myoplasmic [Ca 2+ ] is briefly raised, the inhibitory action of the [Ca 2+ ] regulatory system is temporarily removed, allowing strong, cyclic interactions to occur between myosin cross‐bridges and the actin, fuelled by the hydrolysis of MgATP, and force develops transiently as all the other prerequisites for force generation are present in the fibre (for reviews, see Lüttgau & Stephenson 1986, Stephenson 1988, Ebashi 1991, Ashley et al 1991, Rüegg 1992, Moss et al 1995). One should bear in mind that the Ca 2+ ‐activated contractile apparatus is a major contributor to the production of two major fatiguing factors: P i and protons, which may accumulate during prolonged activation.…”