Differential Effect of Calsequestrin Ablation on Structure and					Function of Fast and Slow Skeletal Muscle Fibers

Paolini, Cecilia; Quarta, Marco; d’Onofrio, Laura; Reggiani, Carlo; Protasi, Feliciano

doi:10.1155/2011/634075

Cited by 28 publications

(48 citation statements)

References 43 publications

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“…CASQ1-null FDB fibers were unable to sustain high level of cytosolic Ca 2ϩ during a tetanus (Fig. 4) in keeping with analogous results obtained in fibers lacking both CASQ1 and 2 (5,36). This represents a likely indication that, in CASQ1-null FDB fibers, the amount of Ca 2ϩ releasable is reduced in relation to a decreased content of SR and that contribution of CASQ2 is not relevant.…”

Section: Phenotype Of Casq1-null Muscle Fibers Of Fdb: Functional Ulsupporting

confidence: 84%

“…Notwithstanding the important functions ascribed to CASQ, genetic ablation of either CASQ1, CASQ2, or both (35,20,45,5,36) was not birth lethal in the mouse. In CASQ1-null mice, contractile responses of muscle fibers were not significantly altered, but there was profound ultrastructural remodeling of CRUs, reduced content of stored Ca 2ϩ , reduced amplitude of Ca 2ϩ transients (35), and inability to support sustained contractile activity (5).…”

mentioning

confidence: 94%

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Calsequestrin (CASQ1) rescues function and structure of calcium release units in skeletal muscles of CASQ1-null mice

Tomasi

Canato

Paolini

et al. 2012

American Journal of Physiology-Cell Physiology

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Amplitude of Ca(2+) transients, ultrastructure of Ca(2+) release units, and molecular composition of sarcoplasmic reticulum (SR) are altered in fast-twitch skeletal muscles of calsequestrin-1 (CASQ1)-null mice. To determine whether such changes are directly caused by CASQ1 ablation or are instead the result of adaptive mechanisms, here we assessed ability of CASQ1 in rescuing the null phenotype. In vivo reintroduction of CASQ1 was carried out by cDNA electro transfer in flexor digitorum brevis muscle of the mouse. Exogenous CASQ1 was found to be correctly targeted to the junctional SR (jSR), as judged by immunofluorescence and confocal microscopy; terminal cisternae (TC) lumen was filled with electron dense material and its width was significantly increased, as judged by electron microscopy; peak amplitude of Ca(2+) transients was significantly increased compared with null muscle fibers transfected only with green fluorescent protein (control); and finally, transfected fibers were able to sustain cytosolic Ca(2+) concentration during prolonged tetanic stimulation. Only the expression of TC proteins, such as calsequestrin 2, sarcalumenin, and triadin, was not rescued as judged by Western blot. Thus our results support the view that CASQ1 plays a key role in both Ca(2+) homeostasis and TC structure.

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Section: Phenotype Of Casq1-null Muscle Fibers Of Fdb: Functional Ulsupporting

confidence: 84%

mentioning

confidence: 94%

Calsequestrin (CASQ1) rescues function and structure of calcium release units in skeletal muscles of CASQ1-null mice

Tomasi

Canato

Paolini

et al. 2012

American Journal of Physiology-Cell Physiology

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“…Therefore, we also determined the impact of Casq deficiency on I SkCRAC magnitude, voltage-dependence, and rate of activation. Since mouse myotubes express both type 1 and type 2 Casq isoforms [26], we compared I SkCRAC magnitude, voltage dependence, and rate of activation in whole-cell voltage clamp experiments of myotubes derived from control WT (C57Bl6) and homozygous dCasq-null [15,27,28] mice (Figures 1 and 2). Similar to that observed for myotubes from Y524S/+ mice, I SkCRAC in dCasq-null myotubes activated rapidly during repetitive depolarization (Figure 1 E), exhibited strong inward rectification (Figure 1 F), and was inhibited by both 1 µM Gd 3+ (59.1 ± 3.9%, n=7) (Figure S1 A in File S1) and 10 µM 2-APB (94.7 ± 8.9%, n = 5) (Figure 1 E and Figure S1 B in File S1).…”

Section: Resultsmentioning

confidence: 99%

“…Since mouse myotubes express both the Casq1 and Casq2 isoforms [26], experiments were conducted in myotubes derived from dCasq-null mice in order to assess the impact of Casq deficiency on I SkCRAC properties. Mice used to generate myotube cultures were genotyped by PCR analysis of tail snip genomic DNA using previously established protocols [10,27]. All electrophysiological experiments were performed on individual myotubes from 8-11 day old cultures.…”

Section: Matherials and Methodsmentioning

confidence: 99%

Accelerated Activation of SOCE Current in Myotubes from Two Mouse Models of Anesthetic- and Heat-Induced Sudden Death

2013

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Store-operated calcium entry (SOCE) channels play an important role in Ca2+ signaling. Recently, excessive SOCE was proposed to play a central role in the pathogenesis of malignant hyperthermia (MH), a pharmacogenic disorder of skeletal muscle. We tested this hypothesis by characterizing SOCE current (ISkCRAC) magnitude, voltage dependence, and rate of activation in myotubes derived from two mouse models of anesthetic- and heat-induced sudden death: 1) type 1 ryanodine receptor (RyR1) knock-in mice (Y524S/+) and 2) calsequestrin 1 and 2 double knock-out (dCasq-null) mice. ISkCRAC voltage dependence and magnitude at -80 mV were not significantly different in myotubes derived from wild type (WT), Y524S/+ and dCasq-null mice. However, the rate of ISkCRAC activation upon repetitive depolarization was significantly faster at room temperature in myotubes from Y524S/+ and dCasq-null mice. In addition, the maximum rate of ISkCRAC activation in dCasq-null myotubes was also faster than WT at more physiological temperatures (35-37°C). Azumolene (50 µM), a more water-soluble analog of dantrolene that is used to reverse MH crises, failed to alter ISkCRAC density or rate of activation. Together, these results indicate that while an increased rate of ISkCRAC activation is a common characteristic of myotubes derived from Y524S/+ and dCasq-null mice and that the protective effects of azumolene are not due to a direct inhibition of SOCE channels.

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“…We postulate that better cardiac function and less rhythm disturbances account for improved exercise capacity in trained KO mice. The impact of CASQ2 deficiency in fast skeletal muscle and the role of muscle conditioning deserve a further study (33). The WT mice were not significantly affected by exercise.…”

Section: Discussionmentioning

confidence: 95%

Exercise training improves cardiac function and attenuates arrhythmia in CPVT mice

Kurtzwald-Josefson

Hochhauser

Katz

et al. 2012

Journal of Applied Physiology

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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal ventricular arrhythmia evoked by physical or emotional stress. Recessively inherited CPVT is caused by either missense or null-allele mutations in the cardiac calsequestrin (CASQ2) gene. It was suggested that defects in CASQ2 cause protein deficiency and impair Ca(2+) uptake to the sarcoplasmic reticulum and Ca(2+)-dependent inhibition of ryanodine channels, leading to diastolic Ca(2+) leak, after-depolarizations, and arrhythmia. To examine the effect of exercise training on left ventricular remodeling and arrhythmia, CASQ2 knockout (KO) mice and wild-type controls underwent echocardiography and heart rhythm telemetry before and after 6 wk of training by treadmill exercise. qRT-PCR and Western blotting were used to measure gene and protein expression. Left ventricular fractional shortening was impaired in KO (33 ± 5 vs. 51 ± 7% in controls, P < 0.05) and improved after training (43 ± 12 and 51 ± 9% in KO and control mice, respectively, P = nonsignificant). The exercise tolerance was low in KO mice (16 ± 1 vs. 29 ± 2 min in controls, P < 0.01), but improved in trained animals (26 ± 2 vs. 30 ± 3 min, P = nonsignificant). The hearts of KO mice had a higher basal expression of the brain natriuretic peptide gene. After training, the expression of natriuretic peptide genes markedly decreased, with no difference between KO and controls. Exercise training was not associated with a change in ventricular tachycardia prevalence, but appeared to reduce arrhythmia load, as manifested by a decrease in ventricular beats during stress. We conclude that, in KO mice, which recapitulate the phenotype of human CPVT2, exercise training is well tolerated and could offer a strategy for heart conditioning against stress-induced arrhythmia.

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Differential Effect of Calsequestrin Ablation on Structure and Function of Fast and Slow Skeletal Muscle Fibers

Cited by 28 publications

References 43 publications

Calsequestrin (CASQ1) rescues function and structure of calcium release units in skeletal muscles of CASQ1-null mice

Calsequestrin (CASQ1) rescues function and structure of calcium release units in skeletal muscles of CASQ1-null mice

Accelerated Activation of SOCE Current in Myotubes from Two Mouse Models of Anesthetic- and Heat-Induced Sudden Death

Exercise training improves cardiac function and attenuates arrhythmia in CPVT mice

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