Mice null for calsequestrin 1 exhibit deficits in functional performance and sarcoplasmic reticulum calcium handling

Rotimi O. Olojo, Andrew P. Ziman, Erick O. Hernández-Ochoa, Paul D. Allen, Martin F. Schneider, Christopher W. Ward

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

In skeletal muscle, the release of calcium (Ca2+) by ryanodine sensitive sarcoplasmic reticulum (SR) Ca2+ release channels (i.e., ryanodine receptors; RyR1s) is the primary determinant of contractile filament activation. Much attention has been focused on calsequestrin (CASQ1) and its role in SR Ca2+ buffering as well as its potential for modulating RyR1, the L-type Ca2+ channel (dihydropyridine receptor, DHPR) and other sarcolemmal channels through sensing luminal [Ca2+]. The genetic ablation of CASQ1 expression results in significant alterations in SR Ca2+ content and SR Ca2+ release especially during prolonged activation. While these findings predict a significant loss-of-function phenotype in vivo, little information on functional status of CASQ1 null mice is available. We examined fast muscle in vivo and in vitro and identified significant deficits in functional performance that indicate an inability to sustain contractile activation. In single CASQ1 null skeletal myofibers we demonstrate a decrease in voltage dependent RyR Ca2+ release with single action potentials and a collapse of the Ca2+ release with repetitive trains. Under voltage clamp, SR Ca2+ release flux and total SR Ca2+ release are significantly reduced in CASQ1 null myofibers. The decrease in peak Ca2+ release flux appears to be solely due to elimination of the slowly decaying component of SR Ca2+ release, whereas the rapidly decaying component of SR Ca2+ release is not altered in either amplitude or time course in CASQ1 null fibers. Finally, intra-SR [Ca2+] during ligand and voltage activation of RyR1 revealed a significant decrease in the SR[Ca2+]free in intact CASQ1 null fibers and a increase in the release and uptake kinetics consistent with a depletion of intra-SR Ca2+ buffering capacity. Taken together we have revealed that the genetic ablation of CASQ1 expression results in significant functional deficits consistent with a decrease in the slowly decaying component of SR Ca2+ release.

Original languageEnglish (US)
Article numbere27036
JournalPLoS One
Volume6
Issue number12
DOIs
StatePublished - Dec 2 2011
Externally publishedYes

Fingerprint

Calsequestrin
sarcoplasmic reticulum
Sarcoplasmic Reticulum
Ryanodine Receptor Calcium Release Channel
Chemical activation
Calcium
calcium
mice
Ablation
Muscle
Electric potential
Fluxes
Ryanodine
L-Type Calcium Channels
Fibers
Clamping devices
Ligands
Kinetics
Action Potentials

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Olojo, R. O., Ziman, A. P., Hernández-Ochoa, E. O., Allen, P. D., Schneider, M. F., & Ward, C. W. (2011). Mice null for calsequestrin 1 exhibit deficits in functional performance and sarcoplasmic reticulum calcium handling. PLoS One, 6(12), [e27036]. https://doi.org/10.1371/journal.pone.0027036

Mice null for calsequestrin 1 exhibit deficits in functional performance and sarcoplasmic reticulum calcium handling. / Olojo, Rotimi O.; Ziman, Andrew P.; Hernández-Ochoa, Erick O.; Allen, Paul D.; Schneider, Martin F.; Ward, Christopher W.

In: PLoS One, Vol. 6, No. 12, e27036, 02.12.2011.

Research output: Contribution to journalArticle

Olojo, RO, Ziman, AP, Hernández-Ochoa, EO, Allen, PD, Schneider, MF & Ward, CW 2011, 'Mice null for calsequestrin 1 exhibit deficits in functional performance and sarcoplasmic reticulum calcium handling', PLoS One, vol. 6, no. 12, e27036. https://doi.org/10.1371/journal.pone.0027036
Olojo, Rotimi O. ; Ziman, Andrew P. ; Hernández-Ochoa, Erick O. ; Allen, Paul D. ; Schneider, Martin F. ; Ward, Christopher W. / Mice null for calsequestrin 1 exhibit deficits in functional performance and sarcoplasmic reticulum calcium handling. In: PLoS One. 2011 ; Vol. 6, No. 12.
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