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1 Department of Zoology, La Trobe University, Melbourne, Victoria, 3086, Australia
In this study we investigated the roles of cytoplasmic ATP as both an energy source and a regulatory molecule in various steps of the excitation–contraction (E–C) coupling process in fast-twitch skeletal muscle fibres of the rat. Using mechanically skinned fibres with functional E–C coupling, it was possible to independently alter cytoplasmic [ATP] and free [Mg2+]. Electrical field stimulation was used to elicit action potentials (APs) within the sealed transverse tubular (T-) system, producing either twitch or tetanic (50 Hz) force responses. Measurements were also made of the amount of Ca2+ released by an AP in different cytoplasmic conditions. The rate of force development and relaxation of the contractile apparatus was measured using rapid step changes in [Ca2+]. Twitch force decreased substantially (
30%) at 2 mM ATP compared to the level at 8 mM ATP, whereas peak tetanic force only declined by 10% at 0.5 mM ATP. The rate of force development of the twitch and tetanus was slowed only slightly at [ATP] 
0.5 mM, but was slowed greatly (> 6-fold) at 0.1 mM ATP, the latter being due primarily to slowing of force development by the contractile apparatus. AP-induced Ca2+ release was decreased by 10 and 20% at 1 and 0.5 mM ATP, respectively, and by 40% by raising the [Mg2+] to 3 mM. Adenosine inhibited Ca2+ release and twitch responses in a manner consistent with its action as a competitive weak agonist for the ATP regulatory site on the ryanodine receptor (RyR). These findings show that (a) ATP is a limiting factor for normal voltage-sensor activation of the RyRs, and (b) large reductions in cytoplasmic [ATP], and concomitant elevation of [Mg2+], substantially inhibit E–C coupling and possibly contribute to muscle fatigue in fast-twitch fibres in some circumstances.
(Received 28 May 2004;
accepted after revision 10 August 2004;
first published online 12 August 2004)
Corresponding author G. D. Lamb: Department of Zoology, La Trobe University, Victoria, 3086, Australia. Email: g.lamb{at}latrobe.edu.au
This article has been cited by other articles:
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  T. L. Dutka, R. M. Murphy, D. G. Stephenson, and G. D. Lamb Chloride conductance in the transverse tubular system of rat skeletal muscle fibres: importance in excitation-contraction coupling and fatigue J. Physiol., February 1, 2008; 586(3): 875 - 887. [Abstract] [Full Text] [PDF]
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 D. G. Allen, G. D. Lamb, and H. Westerblad Skeletal Muscle Fatigue: Cellular Mechanisms Physiol Rev, January 1, 2008; 88(1): 287 - 332. [Abstract] [Full Text] [PDF]
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 D. G. Allen, G. D. Lamb, and H. Westerblad Impaired calcium release during fatigue J Appl Physiol, January 1, 2008; 104(1): 296 - 305. [Abstract] [Full Text] [PDF]
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 B. Bennetts, M. W. Parker, and B. A. Cromer Inhibition of Skeletal Muscle ClC-1 Chloride Channels by Low Intracellular pH and ATP J. Biol. Chem., November 9, 2007; 282(45): 32780 - 32791. [Abstract] [Full Text] [PDF]
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B. S. Launikonis and E. Rios Store-operated Ca2+ entry during intracellular Ca2+ release in mammalian skeletal muscle J. Physiol., August 15, 2007; 583(1): 81 - 97. [Abstract] [Full Text] [PDF]
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T. L. Dutka and G. D. Lamb Transverse tubular system depolarization reduces tetanic force in rat skeletal muscle fibers by impairing action potential repriming Am J Physiol Cell Physiol, June 1, 2007; 292(6): C2112 - C2121. [Abstract] [Full Text] [PDF]
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W. A. Macdonald and D. G. Stephenson Effect of ADP on slow-twitch muscle fibres of the rat: implications for muscle fatigue J. Physiol., May 15, 2006; 573(1): 187 - 198. [Abstract] [Full Text] [PDF]
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G. D. Lamb, D. G. Stephenson, J. Bangsbo, and C. Juel Point:Counterpoint: Lactic acid accumulation is an advantage/disadvantage during muscle activity J Appl Physiol, April 1, 2006; 100(4): 1410 - 1412. [Full Text] [PDF]
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E. Verburg, T. L. Dutka, and G. D. Lamb Long-lasting muscle fatigue: partial disruption of excitation-contraction coupling by elevated cytosolic Ca2+ concentration during contractions Am J Physiol Cell Physiol, April 1, 2006; 290(4): C1199 - C1208. [Abstract] [Full Text] [PDF]
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T. L. Dutka, L. Cole, and G. D. Lamb Calcium phosphate precipitation in the sarcoplasmic reticulum reduces action potential-mediated Ca2+ release in mammalian skeletal muscle Am J Physiol Cell Physiol, December 1, 2005; 289(6): C1502 - C1512. [Abstract] [Full Text] [PDF]
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B. Bennetts, G. Y. Rychkov, H.-L. Ng, C. J. Morton, D. Stapleton, M. W. Parker, and B. A. Cromer Cytoplasmic ATP-sensing Domains Regulate Gating of Skeletal Muscle ClC-1 Chloride Channels J. Biol. Chem., September 16, 2005; 280(37): 32452 - 32458. [Abstract] [Full Text] [PDF]
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T. R Moopanar and D. G Allen Reactive oxygen species reduce myofibrillar Ca2+ sensitivity in fatiguing mouse skeletal muscle at 37{degrees}C J. Physiol., April 1, 2005; 564(1): 189 - 199. [Abstract] [Full Text] [PDF]
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