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J Appl Physiol 96: 645-649, 2004; doi:10.1152/japplphysiol.00481.2003
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Effects of modulators of sarcoplasmic Ca2+ release on the development of skeletal muscle fatigue

E. Germinario,1 A. Esposito,1 A. Megighian,1 M. Midrio,1 R. Betto,2 and D. Danieli-Betto1

1Department of Human Anatomy and Physiology, University of Padova, 35131 Padova; and 2Consiglio Nazionale delle Ricerche Neuroscience Institute, Muscle Biology and Physiopathology Unit, 35121 Padova, Italy

Submitted 7 May 2003 ; accepted in final form 13 October 2003


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The reduced release of Ca2+ from sarcoplasmic reticulum (SR) is considered a major determinant of muscle fatigue. In the present study, we investigated whether the presence of dantrolene, an established inhibitor of SR Ca2+ release, or caffeine, a drug facilitating SR Ca2+ release, modifies muscle fatigue development. Accordingly, the effects of Ca2+ release modulators were analyzed in vitro in mouse fast-twitch [extensor digitorum longus (EDL)] and slow-twitch (soleus) muscles, fatigued by repeated short tetani (40 Hz for 300 ms, 0.5 s-1 in soleus and 60 Hz for 300 ms, 0.3 s-1 in EDL, for 6 min). Caffeine produced a substantial increase of tetanic tension of both EDL and soleus muscles, whereas dantrolene decreased tetanic tension only in EDL muscle. In both EDL and soleus muscles, 5 µM dantrolene did not affect fatigue development, whereas 20 µM dantrolene produced a positive staircase during the first 3 min of stimulation in EDL muscle and a slowing of fatigue development in soleus muscle. The development of the positive staircase was abolished by the addition of 15 µM ML-7, a selective inhibitor of myosin light chain kinase. On the other hand, caffeine caused a larger and faster loss of tension in both EDL and soleus muscles. The results seem to indicate that the changes in fatigue profile induced by caffeine or dantrolene are mainly due to the changes in the initial tetanic tension caused by the drugs, with the resulting changes in the level of contraction-dependent factors of fatigue, rather than to changes in the SR Ca2+ release during fatigue development.

calcium release; muscle tension

MUSCLE FATIGUE IS DEFINED as the failure to maintain the expected or required power output (9). Many factors operate together to cause this failure, the relative importance of each being dependent on the intensity, duration, and nature of the exercise; on the composition of the motor unit involved; and on muscle training.

A reduction of myoplasmic Ca2+ level due to an impairment of sarcoplasmic reticulum (SR) Ca2+ release is considered one of the major causes of muscle fatigue (1, 5, 11, 32, 33). Indeed, a progressive reduction in myoplasmic Ca2+ concentration ([Ca2+]i), accompanying the loss of muscle tension, has been observed under a variety of experimental fatigue conditions (2, 5, 31). The reduced release of Ca2+ from the SR is largely consequent to the profound alterations of metabolite levels caused by the intense muscle work. The accumulation and/or exhaustion of various metabolites not only influence SR Ca2+ release and uptake, but also the sensitivity to Ca2+ of myofibrillar proteins and the tension-generating capacity of contractile elements (1, 32).

Dantrolene is a muscle relaxant, known to decrease contractile force (12) by affecting Ca2+ release from the SR (13, 21, 23-25). The resulting reduction of twitch force is produced without affecting contractile proteins, sliding filament interaction, SR Ca2+ pump activity (7), or membrane properties (10, 30). Many similarities have been reported between the effects of dantrolene and those of fatigue on contractile properties of skeletal muscle (16, 20), reinforcing the view that reduction of SR Ca2+ release participates in causing muscle fatigue. On the other hand, caffeine is a drug known to facilitate Ca2+ release from the SR, thereby increasing [Ca2+]i and force production (3).

If changes in [Ca2+]i play a role in the development of muscle fatigue, the presence of drugs known to affect [Ca2+]i should be expected to modify the time course and the degree of tension failure. In the present work, we examined whether the presence of drugs that modulate Ca2+ release from the SR, such as dantrolene and caffeine, could counteract or enhance the development of fatigue. Indeed, both drugs were able to modify fatigue development. However, on the whole, the results indicate that the changes induced by caffeine and dantrolene on fatigue profile are mainly due to the changes in the initial level of tetanic tension caused by the drugs, rather than to drug-dependent changes in the SR Ca2+ release during fatigue development.


   MATERIALS AND METHODS
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All the experiments were carried out in accordance with the Helsinki Accords for Humane Treatment of Animals during Experimentation. The experimental plan was approved by the Ethics Committee of the Medical Faculty of the University of Padova. This study was performed by using muscles isolated from Swiss mice 3-4 mo of age.

Experimental procedures. The animals were killed with a high dose of ether. Soleus and extensor digitorum longus (EDL) muscles were quickly isolated and immersed in a solution of the following composition (in mM): 119.9 NaCl, 4.7 KCl, 2.5 CaCl2, 3.2 MgCl2, 1.3 NaH2PO4, 2.5 NaHCO3, 11.1 glucose; pH 7.2-7.4. The solution was continuously bubbled with 95% O2-5% CO2. Muscles were then mounted vertically in a bath filled with the same solution, with added 30 µM D-tubocurarine, at 30°C. Muscles were electrically stimulated with supramaximal pulses (0.5-ms duration) delivered by a Grass S44 electronic stimulator through a stimulus-isolation unit (Grass SIU5), and isometric force was recorded with a Grass FT03 force transducer (19). Muscle responses were recorded via an AT-MIO 16 analog-to-digital card and data analyzed by a LabView-based computer program (National Instruments).

Muscles were stretched to the optimal length for twitch tension and allowed to equilibrate for 10 min at 30°C. Normally, twitch parameters (tension, contraction time, and half-relaxation time) were measured before and after the incubation with drugs. Muscles were preincubated with dantrolene (5 or 20 µM, for 10 and 30 min, respectively) or caffeine (2 or 5 mM, for soleus and EDL muscles, respectively, for 30 s). Then muscles were submitted to a 6-min-long fatigue protocol consisting of a train of short tetani at low frequency (40 Hz for 300 ms, 0.5 s-1, in soleus, and 60 Hz for 300 ms, 0.3 s-1 in EDL). Fatigue development was usually analyzed in muscles isolated from one hind leg, whereas the effect of drugs was examined in muscles from the contralateral leg. Tetanic force was expressed in newtons per gram of fresh muscle. Force recorded during the fatigue protocol was normalized to the initial tension. The fatigue index was defined as the ratio between the last and the first tetanus and provided a measure of the percent tension decline resulting from the fatigue protocol. In selected experiments designed to test whether myosin light chain (MLC)-2 phosphorylation influenced fatigue, the MLC-2 kinase inhibitor ML-7 hydrochloride (Calbiochem) was employed.

Two-dimensional analysis of MLCs. MLC composition was analyzed by two-dimensional gel electrophoresis as previously described (6). Briefly, 20 cryostat muscle sections (20 µm) were taken from control and 20 µM dantrolene-treated EDL muscles. The sections were dissolved in 100 µl of 9.5 M urea, 2% (vol/vol) Nonidet NP-40, 5% (vol/vol) 2-mercaptoethanol, 1.0% (vol/vol) Ampholine (Amersham Pharmacia) of pH range 5-7, and 1.0% (vol/vol) Ampholine of pH range 3.5-10, and subjected to isoelectric focusing. The second dimension of the gel consisted of SDS-PAGE in 15% (wt/vol) polyacrylamide slab gels. The gels were then stained with silver staining, and the relative amount of each protein band (MLC isoforms) was determined by densitometry using a Bio-Rad imaging densitometer (GS-670).

Statistical analysis. Values are presented as means ± SE. The statistical significance was tested with Student's t-test for unpaired samples. Differences were considered significant at the P < 0.05 level.


   RESULTS
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Effects of dantrolene and caffeine on twitch tension. Dantrolene affected contractile properties of both soleus and EDL muscles. In the presence of 5 or 20 µM dantrolene, twitch tension was reduced by 32.4 ± 1.4 or 68.6 ± 2.7%, respectively, in EDL muscle, and by 20.3 ± 6.8 or 47.6 ± 4.3% in soleus muscle. The presence of 2 mM (in soleus) and 5 mM caffeine (in EDL) significantly increased the amplitude of the twitch (21.1 ± 4.6% in EDL, n = 4, and 14.0 ± 2.5% in soleus muscles, n = 4). Caffeine (either 2 or 5 mM) did not induce contracture in resting muscles.

Effects of dantrolene on EDL muscle fatigue. In control EDL muscle, tension developed during the fatiguing protocol progressively diminished so that, at the end of stimulation, the fatigue index was 0.388 ± 0.029 (Fig. 1). In the presence of 5 µM dantrolene, the initial 60-Hz tetanic tension decreased significantly (P < 0.01), from 7.2 ± 0.7 N/g in control (n = 4) muscles to 5.0 ± 0.3 N/g with 5 µM dantrolene (n = 6), whereas the time course of fatigue was not affected (fatigue index = 0.357 ± 0.024; Figs. 1 and 2A). In the presence of 20 µM dantrolene, the initial tension was markedly (P < 0.001) reduced (2.1 ± 0.1 N/g, n = 7) with respect to the control values. However, during the first 3 min of stimulation, tension gradually increased, demonstrating a positive staircase which displayed a 60% increase in tension by the end of third minute. Thereafter, tension gradually decreased, reaching the initial level between the fourth and fifth minutes and a slightly lower level at the end of stimulation (fatigue index = 0.811 ± 0.044, P < 0.0001 with respect to controls; Figs. 1 and 2B). Importantly, 15 µM ML-7 nearly abolished the ability of dantrolene to produce the staircase, and no signs of fatigue were evident (Fig. 1).



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  		Fig. 1. Fatigue development in extensor digitorum longus (EDL) muscle. Recordings were obtained from control vehicle-treated muscles ({bullet}, n = 3) and from muscles preincubated with 5 ({triangleup}, n = 4) and 20 µM dantrolene ({square}, n = 4), 20 µM dantrolene + 15 µM ML-7 ({blacksquare}, n = 4), and 5 mM caffeine ({circ}, n = 4). *P < 0.05, **P < 0.005, with respect to the control, §P < 0.05 with respect to 20 µM dantrolene.

 


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  		Fig. 2. Effects of 5 µM dantrolene (A), 20 µM dantrolene (B), and 5 mM caffeine (C) on contractile responses during fatiguing stimulation in EDL muscle. Gray traces are from the treated muscles.

 

Effects of dantrolene on soleus muscle fatigue. In soleus muscle, preincubation with either 5 or 20 µM dantrolene did not significantly modify the initial tetanic force [8.2 ± 0.8 N/g in control (n = 3), 9.5 ± 1.0 N/g in 5 µM dantrolene (n = 3), and 8.1 ± 0.6 N/g in 20 µM dantrolene (n = 5)]. The progressive decline of tetanic tension during the fatiguing stimulation was unaffected with 5 µM dantrolene but significantly slowed in the first 2-3 min with 20 µM dantrolene (Figs. 3 and 4). Fatigue indexes at the sixth minute time points were not modified in the presence of both 5 µM (0.58 ± 0.02) and 20 µM dantrolene (0.58 ± 0.04) with respect to controls (0.57 ± 0.02).



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  		Fig. 3. Fatigue development in soleus muscle. Recordings were obtained from control vehicle-treated muscle ({bullet}, n = 3), from muscles preincubated with 5 ({triangleup}, n = 4) and 20 µM dantrolene ({square}, n = 4), and from muscles preincubated with 2 mM caffeine ({circ}, n = 4) *P < 0.05 with respect to the control.

 


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  		Fig. 4. Effects of 5 µM dantrolene (A), 20 µM dantrolene (B), and 2 mM caffeine (C) on contractile responses during fatiguing stimulation in soleus muscle. Gray traces are from the treated muscles.

 

Effects of caffeine on EDL and soleus muscles fatigue. Caffeine caused a significant (P < 0.05) increase of tetanic tensions in both muscles (10.4 ± 0.6 N/g in EDL, n = 4, and 13.8 ± 1.6 N/g in soleus muscles, n = 4). During fatiguing stimulation, tension of both EDL (Figs. 1 and 2C) and soleus (Figs. 3 and 4C) muscles declined with a steeper slope than in controls. Fatigue indexes at the sixth minute time points were 0.31 ± 0.02 in 5 mM caffeine-treated EDL muscle (P < 0.05 with respect to control) and 0.53 ± 0.01 in 2 mM caffeine-treated soleus muscle.

Two-dimensional analysis of MLCs. Figure 5 shows the phosphorylation level of the regulatory, phosphorylatable, MLC-2 in one control EDL muscle at rest (A), in one 3-min fatigued EDL muscle (B), or in one 3-min fatigued EDL muscle in the presence of 20 µM dantrolene (C). It can be observed that, in the presence of dantrolene, MLC-2 is substantially phosphorylated. Densitometric analyses show that the percentage of phosphorylated MLC-2 was 41.3 ± 2.1 (n = 3) in EDL at rest, 44.0 ± 1.1 (n = 4) in the 3-min fatigued muscle, and 53.4 ± 1.2 (n = 3) in 3-min fatigued muscle in the presence of 20 µM dantrolene (P < 0.01, between the fatigued muscles).



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  		Fig. 5. Two-dimensional analyses of myosin light chain (MLC) isoform composition in 1 control EDL muscle at rest (A) and in 3-min fatigued EDL either in the absence (B) or in the presence (C) of 20 µM dantrolene. Only the MLC region is shown. 1F, 2F, 3F, MLC fast isoforms; 2F-P, phosphorylated MLC-2. Data shown are representative of at least 3 separate experiments.

 


   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Intense and prolonged exercise produces profound modifications of intracellular muscle milieu, leading to the accumulation and the exhaustion of metabolites, which eventually cause the progressive decline of tension production (3, 17, 27). Contraction-dependent factors of fatigue cause tension loss by affecting SR Ca2+ release, sensitivity to Ca2+ of myofibrillar proteins, and tension-generating capacity of contractile elements, with the reduced [Ca2+]i being considered a major contributor to muscle fatigue (4, 11, 27, 32). Here, we studied whether the presence of drugs, caffeine and dantrolene, that modulate Ca2+ release from the SR is able to counteract or to enhance the development of fatigue. In effect, both drugs modified the development of fatigue. However, as a whole, our results indicate that the modifications induced by the two drugs are attributable more to the changes in the initial level of tetanic tension than to changes in SR Ca2+ release during fatigue development.

In EDL muscle, dantrolene caused a reduction of twitch and tetanic tensions, both at 5 µM and, more intensely, at 20 µM. The 5 µM dantrolene did not affect the timing and size of fatigue, whereas 20 µM dantrolene completely abolished the development of fatigue, and, on the contrary, produced a transient potentiation of tension. The lack of fatigue in the presence of 20 µM dantrolene can be reasonably attributable to the strong reduction of the initial tetanic tension, and as a consequence to the smaller accumulation of contraction-dependent factors. It is, however, possible that fatigue development is masked by tension potentiation (17, 26). However, in the presence of ML-7, a specific inhibitor of MLC kinase that eliminated potentiation, no signs of fatigue were evident. It is worth noting that tension potentiation during intermittent stimulation of fast muscle has been attributed to increased phosphorylation of MLC-2 (14, 28), causing a leftward shift of the pCa-tension curve, i.e., an increased Ca2+ sensitivity of myofibrillar elements (29). The positive effect on tension is better appreciated when [Ca2+]i is low and tension at the beginning of stimulation is lower than that observed when maximally activated by Ca2+ (22). This explains the observation that dantrolene facilitates the occurrence of the phenomenon (22), as also confirmed by our experiments. Our results, showing that tension potentiation during stimulation was accompanied by an increase in the level of phosphorylated MLC-2, are in agreement with other data in the literature (18). Moreover, the observation that ML-7 prevents tension potentiation provides a support to the hypothesis concerning the cause of positive staircase.

From our results with high dantrolene concentration, it appears that, in the absence of an adequate initial contraction tension level, the deficiency of myoplasmic Ca2+ is not sufficient per se to induce the development of fatigue.

The lack of effects by 5 µM dantrolene on the development of fatigue in EDL muscle apparently does not support the importance of the strength of contraction, and of Ca2+ deficiency, in causing fatigue. The lower initial tetanic tension should produce reduced contraction-dependent changes of metabolites and then a lower or slowed development of fatigue with respect to the controls. On the other hand, the reduction of initial muscle strength depends only on the reduced SR Ca2+ release caused by the drug (13, 21, 23-25). It may be that, in the presence of 5 µM dantrolene, the effect of reduced contraction-dependent changes of metabolites was enhanced by the reduced availability of myoplasmic Ca2+, resulting in a tension decline during stimulation greater than that expected on the basis of the initial muscle strength. By this point of view, the reduced [Ca2+]i seems to have a role in facilitating the development of fatigue.

The presence of caffeine produced an initial higher tetanic tension both in soleus and EDL muscles. As a consequence, more rapid and intense changes of fatigue metabolites should be expected and, therefore, an anticipated or more marked tension decline. In fact, this happened in both soleus and EDL muscles. It thus appears that during the development of fatigue in the presence of caffeine, the higher [Ca2+]i level is not protective against the negative action of the larger changes of fatigue metabolites.

In soleus muscle, neither 5 nor 20 µM dantrolene reduced the initial tetanic force, although both drug concentrations were effective in reducing twitch tension. The lower ability of dantrolene to affect tetanus tension with respect to twitch tension was also noted by others (15). Thus, in soleus muscle, dantrolene appears less effective in affecting SR Ca2+ release under tetanic stimulation. It is therefore not surprising that fatigue indexes with dantrolene were similar to those of untreated soleus. However, evidence for an action of dantrolene also during tetanic contractions comes from our observation that 20 µM dantrolene significantly slowed fatigue development during the first minutes of stimulation. This slowing effect may indicate that, at the beginning of the fatiguing process, there could be an excess of [Ca2+]i in the muscle, with a negative effect on tension-generation capability, and that dantrolene improved contractile activity by reducing Ca2+ release. It is of interest that the occurrence of a [Ca2+]i increase during the initial phases of a fatiguing stimulation protocol, contrasting with the decrease of developed tension, has been actually demonstrated in both amphibian (2) and mammalian (8, 31) single skeletal muscle fibers.


   GRANTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
The financial support of Telethon Italy (grants 620 to D. Danieli-Betto and 1286 to R. Betto) is gratefully acknowledged. This work was also supported by institutional funds from the Consiglio Nationale delle Ricerche and by a subcontract to National Heart, Lung, and Blood Institute HL-63903 (D. Danieli-Betto).


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. Danieli-Betto, Dept. of Human Anatomy and Physiology, Univ. of Padova, Via Marzolo 3, I-35131 Padova, Italy (E-mail: daniela.danieli{at}unipd.it).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
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  1. Allen DG, Lannergren J, and Westerblad H. Muscle cell function during prolonged activity: cellular mechanisms of fatigue. Exp Physiol 80: 497-527, 1995.[Abstract]
  2. Allen DG, Lee JA, and Westerblad H. Intracellular calcium and tension during fatigue in isolated single muscle fibers from Xenopus laevis. J Physiol 415: 433-458, 1989.[Abstract/Free Full Text]
  3. Allen DG and Westerblad H. The effects of caffeine on intracellular calcium, force and the rate of relaxation of mouse skeletal muscle. J Physiol 487: 331-342, 1995.[Abstract/Free Full Text]
  4. Allen DG and Westerblad H. Role of phosphate and calcium stores in muscle fatigue. J Physiol 536: 657-665, 2001.[Abstract/Free Full Text]
  5. Baker AJ, Longuemare MC, Brandes R, and Weiner MW. Intracellular tetanic calcium signals are reduced in fatigue of whole skeletal muscle. Am J Physiol Cell Physiol 264: C577-C582, 1993.[Abstract/Free Full Text]
  6. Biral D, Damiani E, Volpe P, Salviati G, and Margreth A. Polymorphism of myosin light chains. An electrophoretic and immunological study of rabbit skeletal-muscle myosins. Biochem J 203: 529-540, 1982.[Web of Science][Medline]
  7. Brocklehurst I. Dantrolene sodium and "skinned" muscle fibers (Abstract). Nature 254: 364A, 1975.
  8. Chin ER and Allen DG. The role of elevations in intracellular [Ca2+] in the development of low frequency fatigue in mouse single muscle fibres. J Physiol 491: 813-824, 1996.[Abstract/Free Full Text]
  9. Edwards RHT. Human muscle function and fatigue. In: Human Muscle Fatigue: Physiological Mechanisms, edited by Porter R and Whelan J. London: Pitman Medical, 1981, p. 1-18.
  10. Ellis KO and Bryant SH. Excitation-contraction uncoupling in skeletal muscle by dantrolene sodium. Naunyn Schmiedebergs Arch Pharmacol 274: 107-109, 1972.[CrossRef][Web of Science][Medline]
  11. Favero TG. Sarcoplasmic reticulum Ca2+ release and muscle fatigue. J Appl Physiol 87: 471-483, 1999.[Abstract/Free Full Text]
  12. Flewellen EH, Nelson PE, Jones WP, Arens JF, and Wagner DL. Dantrolene dose response in awake man: implications for management of malignant hyperthermia. Anesthesiology 59: 275-280, 1983.[Web of Science][Medline]
  13. Fruen BR, Mickelson JR, and Louis CF. Dantrolene inhibition of sarcoplasmic reticulum Ca2+ release by direct and specific action at skeletal muscle ryanodine receptors. J Biol Chem 272: 26965-26971, 1997.[Abstract/Free Full Text]
  14. Grange RW, Vandenboom R, and Houston ME. Physiological significance of myosin phosphorylation in skeletal muscle. Can J Appl Physiol 18: 229-242, 1993.[Web of Science][Medline]
  15. Leslie GC and Part NJ. The action of dantrolene sodium on individual fast ad slow motor units of the rat anaesthetized with urethane. Br J Pharmacol 81: 351-360, 1984.[Web of Science]
  16. MacIntosh BR. Skeletal muscle staircase response with fatigue or dantrolene sodium. Med Sci Sports Exerc 23: 56-63, 1991.
  17. MacIntosh BR and Rassier DE. What is fatigue? Can J Appl Physiol 27: 42-55, 2002.[Web of Science][Medline]
  18. Manning DR and Stull JT. Myosin light chain phosphorylation-dephosphorylation in mammalian skeletal muscle. Am J Physiol Cell Physiol 242: C234-C241, 1982.[Abstract/Free Full Text]
  19. Midrio M, Danieli Betto D, Megighian A, and Betto R. Early effects of denervation on sarcoplasmic reticulum properties of slow-twitch rat muscle fibres. Pflügers Arch 434: 398-405, 1997.[CrossRef][Web of Science][Medline]
  20. Moussavi RS, Lehamn SL, and Miller RG. Dantrolene sodium and fatigue of long duration. Muscle Nerve 15: 384-389, 1992.[CrossRef][Web of Science][Medline]
  21. Nelson TJ, Zhao WQ, Yuan S, Favit A, Pozzo-Miller L, and Alkon DL. Calcexcitin interaction with neuronal ryanodine-receptors. Biochem J 341: 423-433, 1996.[CrossRef]
  22. Palmer BM and Moore RL. Myosin light chain phosphorylation and tension potentiation in mouse skeletal muscle. Am J Physiol Cell Physiol 257: C1012-C1019, 1989.[Abstract/Free Full Text]
  23. Palnitkar SS, Mickelson CF, Louis CF, and Parness J. Pharmacological distinction between dantrolene and ryanodine binding sites: evidence from normal and malignant hyperthermia-susceptible porcine skeletal muscle. Biochem J 326: 847-852, 1997.[Medline]
  24. Parness J and Palnitkar SS. Identification of dantrolene binding sites in porcine skeletal muscle sarcoplasmic reticulum. J Biol Chem 270: 18465-18472, 1955.
  25. Pessah IN, Lynch C, and Gronert GA. Complex pharmacology of malignant hyperthermia. Anesthesiology 84: 1275-1279, 1966.
  26. Rassier DE and MacIntosh BR. Coexistence of potentiation and fatigue in skeletal muscle. Braz J Med Biol Res 33: 499-508, 2000.[Web of Science][Medline]
  27. Steele DS and Duke AM. Metabolic factors contributing to altered Ca2+ regulation in skeletal muscle fatigue. Acta Physiol Scand 179: 39-48, 2003.[CrossRef][Web of Science][Medline]
  28. Sweeney HL, Bowman BF, and Stull JT. Myosin light chain phosphorylation in vertebrate striated muscle: regulation and function. Am J Physiol Cell Physiol 264: C1085-C1095, 1993.[Abstract/Free Full Text]
  29. Sweeney HL and Stull JT. Phosphorylation of myosin in permeabilized mammalian cardiac and skeletal muscle cells. Am J Physiol Cell Physiol 250: C657-C660, 1986.[Abstract/Free Full Text]
  30. Szentesi P, Collet C, Sarkozi S, Szegedi C, Jona I, Jacquemond V, Kovacs L, and Csernoch L. Effects of dantrolene on steps of excitation-contraction coupling in mammalian skeletal fibers. J Gen Physiol 118: 355-375, 2001.[Abstract/Free Full Text]
  31. Westerblad H and Allen DG. Changes of myoplasmic calcium concentration during fatigue in single mouse muscles fibers. J Gen Physiol 98: 615-635, 1991.[Abstract/Free Full Text]
  32. Westerblad H, Allen DG, and Lannergren J. Muscle fatigue: lactic acid or inorganic phosphate the major cause? News Physiol Sci 17: 17-21, 2002.[Abstract/Free Full Text]
  33. Williams JH and Klug GA. Calcium exchange hypothesis of skeletal muscle fatigue: a brief review. Muscle Nerve 18: 421-434, 1995.[CrossRef][Web of Science][Medline]



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