Mechanisms underlying changes of tetanic [Ca2+]i and force in skeletal muscle
Abstract
Force development in skeletal muscle is driven by an increase in myoplasmic free [Ca 2+] ([Ca 2+]i) due to Ca 2+ release from the sarcoplasmic reticulum (SR). The magnitude of [Ca 2+]i elevation during stimulation depends on: (a) the rate of Ca 2+ release from the SR, (b) the rate of Ca 2+ uptake by the SR, and (c) the myoplasmic Ca 2+ buffering. We have used fluorescent Ca 2+ indicators to measure [Ca 2+]i in intact, single fibres from mouse and Xenopus muscles under conditions where one or more of the above factors are changed. The following interventions resulted in increased tetanic [Ca 2+]i: β‐adrenergic stimulation, which potentiates the SR Ca 2+ release; application of 2,5‐di(tert‐butyl)‐1,4‐benzohydroquinone, which inhibits SR Ca 2+ pumps; application of caffeine, which facilitates SR Ca 2+ release and inhibits SR Ca 2+ uptake; early fatigue, where the rate of SR Ca 2+ uptake is reduced; acidosis, which reduces both the myoplasmic Ca 2+ buffering and the rate of SR Ca 2+ uptake. Reduced tetanic [Ca 2+]i was observed in late fatigue, due to reduced SR Ca 2+ release, and in alkalosis, due to increased myoplasmic Ca 2+ buffering. Force is monotonically related to [Ca 2+]i, but depends also on the myofibrillar Ca 2+ sensitivity and the maximum force cross‐bridges can produce. This is clearly illustrated by changes of intracellular pH where, despite a lower tetanic [Ca 2+]i, tetanic force is higher in alkalosis than acidosis due to increases of myofibrillar Ca 2+ sensitivity and maximum cross‐bridge force.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The reduction in muscle force in myopathy mice is likely caused by deficient formation of force-generating actin-myosin cross bridges and/or disregulation of Ca2+ homeostasis.
“This reduction in muscle force is likely caused by deficient formation of force-generating actin-myosin cross bridges and͞or disregulation of Ca 2؉ homeostasis.”
From Increased mitochondrial mass in mitochondrial myopathy mice (2002) · cites this paper as [32]
Cited by
Sorted by citations
Coexistence of potentiation and fatigue in skeletal muscle
Rassier, D. E., & MacIntosh, B. R. (2000) · Brazilian Journal of Medical and Biological Research · doi:10.1590/s0100-879x2000000500003 · Cited by 490 · see citing works
Reid, M. B., Lännergren, J., & Westerblad, H. (2002) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.2202005 · Cited by 322 · see citing works
Self-citationIncreased mitochondrial mass in mitochondrial myopathy mice
Wredenberg, A., Wibom, R., Wilhelmsson, H., Graff, C., Wiener, H. H., Burden, S. J., Oldfors, A., Westerblad, H., & Larsson, N.-G. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.232591499 · Cited by 302 · see citing works
Self-citationEffect of caffeine on the neuromuscular system — potential as an ergogenic aid
Tarnopolsky, M. A. (2008) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/h08-121 · Cited by 187 · see citing works
“, caffeine could partially restore the loss of force following such types of fatigue) (Allen and Westerblad 1995; Westerblad and Allen 1996).”
BackgroundAndrade, F. H., Reid, M. B., & Westerblad, H. (2000) · The FASEB Journal · doi:10.1096/fj.00-0507fje · Cited by 181 · see citing works
“There are three principal mechanisms by which tetanic [Ca 2+]i may be altered: changes in SR Ca 2+ release, changes in SR Ca2+ re-uptake, and changes in myoplasmic Ca2+ buffering ( 28 ).”
BackgroundSelf-citationDíaz, F., Thomas, C. K., García, S., Hernandez, D., & Moraes, C. T. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi307 · Cited by 179 · see citing works
“Tetanic forces were reduced more than twitch forces in controls, whereas both forces had similar reductions in the COX10 KO, suggesting problems of calcium release (31).”
BackgroundUnilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia
Sluka, K. A., Kalra, A., & Moore, S. A. (2001) · Muscle & Nerve · doi:10.1002/1097-4598(200101)24:1 · Cited by 502 · see citing works
Effect of nitric oxide on single skeletal muscle fibres from the mouse
Andrade, F. H., Reid, M. B., Allen, D. G., & Westerblad, H. (1998) · The Journal of Physiology · doi:10.1111/j.1469-7793.1998.577bn.x · Cited by 133 · see citing works
“[Ca¥]é during the present type of brief tetanic contractions depends on the myoplasmic Ca¥ buffering, the rate of SR Ca¥ uptake, and the SR Ca¥ release (Westerblad & Allen, 1996).”
BackgroundSelf-citationCaffeine and creatine use in sport
Tarnopolsky, M. A. (2010) · Annals of Nutrition and Metabolism · doi:10.1159/000322696 · Cited by 130 · see citing works
“Low-frequency fatigue is felt to occur at the level of calcium release from the sarcoplasmic reticulum [”
BackgroundPhysiology of intracellular calcium buffering
Eisner, D. A., Neher, E., Taschenberger, H., & Smith, G. L. (2023) · Physiological Reviews · doi:10.1152/physrev.00042.2022 · Cited by 158 · see citing works
Sarcoplasmic reticulum Ca2+release and muscle fatigue
Favero, T. G. (1999) · Journal of Applied Physiology · doi:10.1152/jappl.1999.87.2.471 · Cited by 123 · see citing works
Enhanced sarcoplasmic reticulum Ca<sup>2+</sup>release following intermittent sprint training
Ørtenblad, N., Lunde, P. K., Levin, K., Andersen, J. L., & Pedersen, P. K. (2000) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2000.279.1.r152 · Cited by 114 · see citing works
Reliability of techniques to assess human neuromuscular function in vivo
Clark, B. C., Cook, S. B., & Ploutz-Snyder, L. L. (2007) · Journal of Electromyography and Kinesiology · doi:10.1016/j.jelekin.2005.11.008 · Cited by 107 · see citing works
Hostrup, M., & Bangsbo, J. (2016) · The Journal of Physiology · doi:10.1113/jp273218 · Cited by 100 · see citing works
“…from the myoplasm into the SR, which predominantly is controlled by the Ca2+ uptake rate of SR Ca2+-ATPase isoforms SERCAI and SERCAII, but also by the dissociation off-kinetics of troponin C, and the Ca2+ loading rate of Ca2+-binding proteins (Westerblad & Allen, 1996a,b; Nogueira et al. 2013).”
BackgroundCheng, A. J., Bruton, J. D., Lanner, J. T., & Westerblad, H. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2014.279398 · Cited by 86 · see citing works
Self-citationNeuromuscular plasticity during and following 3 wk of human forearm cast immobilization
Clark, B. C., Issac, L. C., Lane, J. L., Damron, L. A., & Hoffman, R. L. (2008) · Journal of Applied Physiology · doi:10.1152/japplphysiol.90530.2008 · Cited by 82 · see citing works
Bruton, J. D., Tavi, P., Aydin, J., Westerblad, H., & Lännergren, J. (2003) · The Journal of Physiology · doi:10.1111/j.1469-7793.2003.00179.x · Cited by 78 · see citing works
“Changes in the removal of Ca2+ by the SR were monitored by measuring the mean [Ca2+]i over a 100 ms period (50–150 ms) during the decay phase of the tetanic Ca2+ transient (Westerblad & Allen, 1996).”
MethodSelf-citationEffect of 10‐day cast immobilization on sarcoplasmic reticulum calcium regulation in humans
Thom, J. M., Thompson, M. W., Ruell, P. A., Bryant, G., Fonda, J. S., Harmer, A. R., de Jonge, X. J., & Hunter, S. K. (2001) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.2001.00853.x · Cited by 77 · see citing works
Increased mitochondrial Ca 2+ and decreased sarcoplasmic reticulum Ca 2+ in mitochondrial myopathy
Aydin, J., Andersson, D. C., Hänninen, S. L., Wredenberg, A., Tavi, P., Park, C. B., Larsson, N.-G., Bruton, J. D., & Westerblad, H. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddn355 · Cited by 75 · see citing works
Self-citationImpaired sarcoplasmic reticulum Ca2+release rate after fatiguing stimulation in rat skeletal muscle
Ørtenblad, N., Sjøgaard, G., & Madsen, K. (2000) · Journal of Applied Physiology · doi:10.1152/jappl.2000.89.1.210 · Cited by 73 · see citing works
Modulation of the actomyosin interaction during fatigue of skeletal muscle
Cooke, R. (2007) · Muscle & Nerve · doi:10.1002/mus.20891 · Cited by 73 · see citing works
Lunde, P., Dahlstedt, A. J., Bruton, J. D., Lännergren, J., Thorén, P., Sejersted, O. M., & Westerblad, H. (2001) · Circulation Research · doi:10.1161/hh1201.092041 · Cited by 71 · see citing works
Self-citationBruton, J. D., Tavi, P., Aydin, J., Westerblad, H., & Lännergren, J. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2003.043927 · Cited by 63 · see citing works
Self-citationSkurvydas, A., Mamkus, G., Kamandulis, S., Dudonienė, V., Valančienė, D., & Westerblad, H. (2016) · European Journal of Applied Physiology · doi:10.1007/s00421-016-3473-0 · Cited by 63 · see citing works
Self-citationAbbate, F., Bruton, J. D., De Haan, A., & Westerblad, H. (2002) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00416.2001 · Cited by 53 · see citing works
“kinetic correction is limited during the tetanic plateau (23).”
BackgroundSelf-citationLännergren, J., Westerblad, H., & Bruton, J. D. (2001) · Journal of Muscle Research and Cell Motility · doi:10.1023/a:1012227009544 · Cited by 47 · see citing works
Self-citationSphingosine 1-phosphate protects mouse extensor digitorum longus skeletal muscle during fatigue
Danieli‐Betto, D., Germinario, E., Esposito, A., Megighian, A., Midrio, M., Ravara, B., Damiani, E., Libera, L. D., Sabbadini, R. A., & Betto, R. (2005) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00246.2004 · Cited by 46 · see citing works
“about the same initial tetanic tension (N/g), to avoid the effects produced by different accumulation-depletion of metabolites during fatigue (17, 50).”
BackgroundIncreased susceptibility to fatigue of slow- and fast-twitch muscles from mice lacking the MG29 gene
NAGARAJ, R. Y., Nosek, C. M., Brotto, M. A. P., Nishi, M., Takeshima, H., Nosek, T. M., & Ma, J. (2000) · Physiological Genomics · doi:10.1152/physiolgenomics.2000.4.1.43 · Cited by 45 · see citing works
Nogueira, L., Trisko, B. M., Lima‐Rosa, F. L., Jackson, J., Lund‐Palau, H., Yamaguchi, M., & Breen, E. C. (2018) · The Journal of Physiology · doi:10.1113/jp275888 · Cited by 44 · see citing works
Même, W., Huchet, C., & Léoty, C. (1998) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1998.274.1.c253 · Cited by 40 · see citing works
Toxic doses of caffeine are needed to increase skeletal muscle contractility
Neyroud, D., Cheng, A. J., Donnelly, C., Bourdillon, N., Gassner, A., Geiser, L., Rudaz, S. L., Kayser, B., Westerblad, H., & Place, N. (2018) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00269.2018 · Cited by 39 · see citing works
Self-citationSkeletal muscle redox signaling in rheumatoid arthritis
Steinz, M. M., Alves, E. S., & Lanner, J. T. (2020) · Clinical Science · doi:10.1042/cs20190728 · Cited by 37 · see citing works
Effects of Congestive Heart Failure on Ca 2+ Handling in Skeletal Muscle During Fatigue
Lunde, P., Sejersted, O. M., Thorud, H.-M. S., et al. (2006) · Circulation Research · doi:10.1161/01.res.0000226529.66545.e5 · Cited by 36 · see citing works
Self-citationDuke, A. M., & Steele, D. S. (1999) · The Journal of Physiology · doi:10.1111/j.1469-7793.1999.0447t.x · Cited by 35 · see citing works
Calmodulin kinase modulates Ca2+ release in mouse skeletal muscle
Tavi, P., Allen, D. G., Niemelä, P. S., Vuolteenaho, O. J., Weckström, M., & Westerblad, H. (2003) · The Journal of Physiology · doi:10.1111/j.1469-7793.2003.00005.x · Cited by 37 · see citing works
Self-citationMitochondrial function in intact skeletal muscle fibres of creatine kinase deficient mice
Bruton, J. D., Dahlstedt, A. J., Abbate, F., & Westerblad, H. (2003) · The Journal of Physiology · doi:10.1111/j.1469-7793.2003.00393.x · Cited by 34 · see citing works
“This uncoupling between tetanic [Ca2+]i and force obviously reflects a marked decrease in myofibrillar Ca2+ sensitivity and/or reduced ability of cross-bridges to generate force (Westerblad & Allen, 1996).”
BackgroundSelf-citationCalmodulin kinase modulates Ca2+ release in mouse skeletal muscle
Tavi, P., Allen, D. G., Niemelä, P. S., et al. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2003.042002 · Cited by 27 · see citing works
Self-citationWahr, P. A., & Metzger, J. M. (1999) · Biophysical Journal · doi:10.1016/s0006-3495(99)77371-6 · Cited by 26 · see citing works
Brotto, M., Leyen, S. A., Nosek, C. M., et al. (2000) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s004240000327 · Cited by 25 · see citing works
MacFarlane, N. G., Darnley, G. M., & Smith, G. L. (2000) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.2000.278.4.c739 · Cited by 25 · see citing works
The physiology of inflammatory myopathies: an overview
Lundberg, I. E. (2001) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.2001.00822.x · Cited by 25 · see citing works
Mikkelsen, U. R., Gissel, H., Fredsted, A., et al. (2005) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00392.2005 · Cited by 23 · see citing works
“This functional defect may be attributed to the following: 1) rundown of transmembrane Na -K -gradients and depolarization leading to loss of excitability (2, 17); 2) loss of energy supplies (14), 3) impaired release of Ca(2) from the sarcoplasmic reticulum or reduced myofibrillar Ca(2) sensitivity (6, 31, 34); 4) int…”
BackgroundNogueira, L., Shiah, A. A., Gandra, P. G., & Hogan, M. C. (2013) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00178.2013 · Cited by 24 · see citing works
Mitochondrial function in intact skeletal muscle fibres of creatine kinase deficient mice
Bruton, J. D. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2003.050732 · Cited by 21 · see citing works
Contractile function is unaltered in diaphragm from mice lacking calcium release channel isoform 3
Clancy, J. S., Takeshima, H., Hamilton, S. L., et al. (1999) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1999.277.4.r1205 · Cited by 20 · see citing works
Do changes in muscle architecture affect post-activation potentiation?
Reardon, D., Hoffman, J. R., Mangine, G. T., Wells, A. J., Gonzalez, A. M., Jajtner, A. R., Townsend, J. R., McCormack, W. P., Stout, J. R., Fragala, M. S., et al. (2014) · PubMed Central · Cited by 18 · see citing works
Mechanisms of Skeletal Muscle Weakness
Westerblad, H., Place, N., & Yamada, T. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-6366-6_16 · Cited by 16 · see citing works
Self-citationCardiac SERCA activity in sockeye salmon populations: an adaptive response to migration conditions
Anttila, K., Farrell, A. P., Patterson, D. A., et al. (2018) · Canadian Journal of Fisheries and Aquatic Sciences · doi:10.1139/cjfas-2018-0334 · Cited by 15 · see citing works
“The intuitive explanation of this result is that SERCA is more important for stroke work (stroke volume × mean arterial pressure) than heart rate because the force of cardiac muscle contraction depends partly upon how much Ca2+ is cycled between contractions (e.g., Westerblad and Allen 1996).”
BackgroundAnttila, K. (2009) · Cited by 14 · see citing works
Nogueira, L., Gilmore, N. K., & Hogan, M. C. (2022) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00861.2021 · Cited by 10 · see citing works
Metabolic alkalosis and myoclonus
Simons, P., Nadra, I. J., & McNally, P. G. (2003) · Postgraduate Medical Journal · doi:10.1136/pmj.79.933.414 · Cited by 8 · see citing works
Kim, S.-B., Kim, J., Park, S.-W., et al. (2012) · International Journal of Precision Engineering and Manufacturing · doi:10.1007/s12541-012-0222-0 · Cited by 8 · see citing works
Uurasmaa, T., Streng, T., Alkio, M., HEINONEN, I. H. A., & Anttila, K. (2021) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-021-00830-z · Cited by 8 · see citing works
“at which myosin and actin can interact [26].”
BackgroundDevelopment and Evaluation of a Bio-ion Measurement System on Acupoints for Meridian Diagnosis
Kim, S.-B., Shin, T., & Lee, Y. (2013) · Journal of Acupuncture and Meridian Studies · doi:10.1016/j.jams.2012.12.005 · Cited by 8 · see citing works
Kim, S.-B., Kim, J., Park, S.-W., et al. (2013) · Acupuncture & Electro-Therapeutics Research · doi:10.3727/036012912x13831831256294 · Cited by 7 · see citing works
“Moreover, some phenomenon were observed in an acupoint such as sarcoplasmic Ca release, the impairment of reuptake and the disturbance of electrolyte concentrations [48-50] under the influence of fatigue.”
Contractile properties of skeletal muscle fibre bundles from mice deficient in carbonic anhydrase II
Beekley, M. D., Wetzel, P., Kubis, H., et al. (2006) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-006-0048-7 · Cited by 6 · see citing works
Ion-dependence of Z-line and M-line response to calcium in striated muscle fibres in rigor
Coomber, S. J., Taracewicz, E., Akhtar, S., deHaan, A., & ELLIOTT, G. F. (2001) · Cell Calcium · doi:10.1054/ceca.2001.0237 · Cited by 5 · see citing works
OpiCa1 reduces inflammation and ROS levels counteracting heat stress-induced cardiac injury
Yang, Z., Hua, X., Wang, F., et al. (2025) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2025.177711 · Cited by 4 · see citing works
Ribeiro, F. A. D. S., Bertucci, D. R., Kalva‐Filho, C. A., de Arruda, T. B., Norberto, M. S., Raspantini, G. L., de Freitas, E. C., Zagatto, A. M., & Papoti, M. (2024) · International journal of exercise science · doi:10.70252/jsrh7021 · Cited by 1 · see citing works
Bartels, E. M. (2016) · Pan Stanford Publishing Pte. Ltd. eBooks · doi:10.1201/9781315364674-4 · Cited by 1 · see citing works
Authorised EU health claim for glycaemic carbohydrates and muscular recovery
Chappuis, E. (2017) · Elsevier eBooks · doi:10.1016/b978-0-08-100922-2.00009-7 · Cited by 1 · see citing works
Bruce, C. D., Debenham, M. I. B., Dalton, B. H., et al. (2024) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00378.2024 · Cited by 1 · see citing works
human forearm cast immobilization Neuromuscular plasticity during and following 3 wk of
Clark, B. C., Issac, L. C., Lane, J., Damron, L. A., Richard, L., Mahato, N. K., Nakazawa, M., Law, T., Thomas, J. S., Østergaard, L., et al. (2015)
invited review Sarcoplasmic reticulum Ca 21 release and muscle fatigue
Favero, T. G. (1999)
Glass, L. D. (2017) · Libraries and Cultural Resources (University of Calgary) · doi:10.11575/prism/28320
A case report of a COPD patient presented in severe metabolic alkalosis
Shrestha, A., Gurung, N., Karthak, A., Bhattarai, S., Lama, R., Shrestha, U. K., Khanal, K., Ghimire, A., Regmi, A., & Shrestha, S. K. (2022) · Nepalese Respiratory Journal · doi:10.3126/nrj.v1i2.54936
- Authors
- WESTERBLAD, H., & ALLEN, D. G.
- Affiliations
- Karolinska Institutet (SE)
- The University of Sydney (AU)
- Corresponding author
- WESTERBLAD, H.
- Venue
- Acta Physiologica Scandinavica
- Publisher
- Wiley
- Published
- 1996-03
- Volume
- 156
- Issue
- 3
- Pages
- 407-416
- ISSN
- 0001-6772 (ISSN-L)
- 1365-201X
- OpenAlex
- W2128224982
- Cited by
- 64
- References
- 0
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 1 · 2018: 3 · 2017: 2 · 2016: 3 · 2015: 1 · 2014: 2 · 2013: 3 · 2012: 1
- FWCI
- 0.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Acta Physiologica Scandinavica (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- sarcoplasmic reticulum calcium release, sarcoplasmic reticulum calcium uptake, beta-adrenergic stimulation, caffeine, muscle fatigue, acidosis, alkalosis, intracellular pH, myofibrillar calcium sensitivity, single muscle fibers
- MeSH terms
- Animals, Calcium, Humans, Muscle Contraction, Muscle, Skeletal, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
