Intracellular Ca2+ transients in delta-sarcoglycan knockout mouse skeletal muscle

Solares-Pérez, Alhondra; Sánchez, Jorge A.; Zentella‐Dehesa, Alejandro; García, Maria C.; Coral‐Vázquez, Ramón Mauricio

doi:10.1016/j.bbagen.2009.11.011

Cited by 6 publications

(8 citation statements)

References 31 publications

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“…δ-SG3 lacks 122 C-terminal amino acids of full-length δ-SG, including the conserved Cys-rich extracellular domain. The C-terminus of δ-SG3 consists of 10 amino acids, which are encoded by a newly identified exon 5b [26, 50]. While we demonstrate protein expression of nSPN, μSPN, and SG isoforms in the SR, it is unclear whether these proteins form a subcomplex within these intracellular membrane structures.…”

Section: Discussionmentioning

confidence: 73%

“…The enlargement on the upper right represents a schematic illustration of the SR membranes where nSPN and μSPN (color scheme as described in Fig. 1) are enriched and associate with a subset of the SGs (δ-SG, δ-SG3, and γ-SG; orange ) [26, 50]. Triadic SR regions contain δ-SG3, nSPN, and μSPN ( lower enlargement ), but lack δ-SG and γ-SG as previously described [26, 50].…”

Section: Discussionmentioning

confidence: 99%

“…1) are enriched and associate with a subset of the SGs (δ-SG, δ-SG3, and γ-SG; orange ) [26, 50]. Triadic SR regions contain δ-SG3, nSPN, and μSPN ( lower enlargement ), but lack δ-SG and γ-SG as previously described [26, 50]. Data from two-photon laser scanning microscopy reveals that nSPN is mostly associated with the ZSR and the triadic SR, and only minimally with the LSR.…”

Section: Discussionmentioning

confidence: 99%

“…9). This hypothesis is further strengthened by the observation that both the murine and hamster models of δ-SG deficiency display aberrant intracellular Ca 2+ handling in skeletal muscle [26, 50, 51]. Future studies will focus on determining whether the SG-SSPN isoforms that are localized to the SR truly form a subcomplex and whether perturbations in the complex affect intracellular Ca 2+ levels.…”

Section: Discussionmentioning

confidence: 99%

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Nanospan, an alternatively spliced isoform of sarcospan, localizes to the sarcoplasmic reticulum in skeletal muscle and is absent in limb girdle muscular dystrophy 2F

et al. 2017

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BackgroundSarcospan (SSPN) is a transmembrane protein that interacts with the sarcoglycans (SGs) to form a tight subcomplex within the dystrophin-glycoprotein complex that spans the sarcolemma and interacts with laminin in the extracellular matrix. Overexpression of SSPN ameliorates Duchenne muscular dystrophy in murine models.MethodsStandard cloning approaches were used to identify nanospan, and nanospan-specific polyclonal antibodies were generated and validated. Biochemical isolation of skeletal muscle membranes and two-photon laser scanning microscopy were used to analyze nanospan localization in muscle from multiple murine models. Duchenne muscular dystrophy biopsies were analyzed by immunoblot analysis of protein lysates as well as indirect immunofluorescence analysis of muscle cryosections.ResultsNanospan is an alternatively spliced isoform of sarcospan. While SSPN has four transmembrane domains and is a core component of the sarcolemmal dystrophin-glycoprotein complex, nanospan is a type II transmembrane protein that does not associate with the dystrophin-glycoprotein complex. We demonstrate that nanospan is enriched in the sarcoplasmic reticulum (SR) fractions and is not present in the T-tubules. SR fractions contain membranes from three distinct structural regions: a region flanking the T-tubules (triadic SR), a SR region across the Z-line (ZSR), and a longitudinal SR region across the M-line (LSR). Analysis of isolated murine muscles reveals that nanospan is mostly associated with the ZSR and triadic SR, and only minimally with the LSR. Furthermore, nanospan is absent from the SR of δ-SG-null (Sgcd−/−) skeletal muscle, a murine model for limb girdle muscular dystrophy 2F. Analysis of skeletal muscle biopsies from Duchenne muscular dystrophy patients reveals that nanospan is preferentially expressed in type I (slow) fibers in both control and Duchenne samples. Furthermore, nanospan is significantly reduced in Duchenne biopsies.ConclusionsAlternative splicing of proteins from the SG-SSPN complex produces δ-SG3, microspan, and nanospan that localize to the ZSR and the triadic SR, where they may play a role in regulating resting calcium levels as supported by previous studies (Estrada et al., Biochem Biophys Res Commun 340:865–71, 2006). Thus, alternative splicing of SSPN mRNA generates three protein isoforms (SSPN, microspan, and nanospan) that differ in the number of transmembrane domains affecting subcellular membrane association into distinct protein complexes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-017-0127-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Nanospan, an alternatively spliced isoform of sarcospan, localizes to the sarcoplasmic reticulum in skeletal muscle and is absent in limb girdle muscular dystrophy 2F

et al. 2017

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“…No apparent differences in the levels of expression of various Ca 2+ handling proteins (DHPR, RyR, SR Ca 2+ ATPase, and Na + /Ca 2+ exchanger), muscle-specific proteins (contractile actin and acetyl-choline receptor), or DGC member proteins except SGs and SSPN have been reported [46]. Furthermore, SOC channel abnormalities have been described in the δ-SG KO mouse model [47]. …”

Section: Discussionmentioning

confidence: 99%

Altered calcium pump and secondary deficiency of γ-sarcoglycan and microspan in sarcoplasmic reticulum membranes isolated from δ-sarcoglycan knockout mice

Solares-Pérez

Álvarez²,

Crosbie

et al. 2010

Cell Calcium

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Sarcoglycans (SGs) and sarcospan (SSPN) are transmembrane proteins of the dystrophin-glycoprotein complex. Mutations in the genes encoding SGs cause many inherited forms of muscular dystrophy. In this study, using purified membranes of wild-type (WT) and δ-SG knockout (KO) mice, we found the specific localization of the SG-SSPN isoforms in transverse tubules (TT) and sarcoplasmic reticulum (SR) membranes. Immunoblotting revealed that the absence of δ-SG isoforms in TT and SR results in a secondary deficiency of γ-SG and µSPN. Our results showed augmented ATP hydrolytic activity, ATP-dependent calcium uptake and passive calcium efflux, probably through SERCA1 in KO compared to WT mice. Furthermore, we found a conformational change in SERCA1 isolated from KO muscle as demonstrated by calorimetric analysis. Following these alterations with mechanical properties, we found an increase in force in KO muscle with the same rate of fatigue but with a decreased fatigue recovery compared to WT. Together our observations suggest, for the first time, that the δ-SG isoforms may stabilize the expression of γ-SG and µSPN in the TT and SR membranes and that this possible complex may play a role in the maintenance of a stable level of resting cytosolic calcium concentration in skeletal muscle.

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Nitrosative stress elicited by nNOSµ delocalization inhibits muscle force in dystrophin‐null mice

Yue

Lai

et al. 2010

The Journal of Pathology

122

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The mechanism of force reduction is not completely understood in Duchenne muscular dystrophy (DMD), a dystrophin-deficient lethal disease. Nitric oxide regulates muscle force. Interestingly, neuronal nitric oxide synthase μ (nNOSμ), a major source of muscle nitric oxide, is lost from the sarcolemma in DMD muscle. We hypothesize that nNOSμ delocalization contributes to force reduction in DMD. To test this hypothesis, we generated dystrophin/nNOSμ double knockout mice. Genetic elimination of nNOSμ significantly enhanced force in dystrophin-null mice. Pharmacological inhibition of nNOS yielded similar results. To further test our hypothesis, we studied δ-sarcoglycan-null mice, a model of limb-girdle muscular dystrophy. These mice had minimal sarcolemmal nNOSμ delocalization and muscle force was less compromised. Annihilation of nNOSμ did not improve their force either. To determine whether nNOSμ delocalization itself inhibited force, we corrected muscle disease in dystrophin-null mice with micro-dystrophins that either restored or did not restore sarcolemmal nNOSμ. Similar muscle force was obtained irrespective of nNOSμ localization. Additional studies suggest that nNOSμ delocalization selectively inhibits muscle force in dystrophin-null mice via nitrosative stress. In summary, we have demonstrated for the first time that nitrosative stress elicited by nNOSμ delocalization is an important mechanism underlying force loss in DMD.

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Intracellular Ca2+ transients in delta-sarcoglycan knockout mouse skeletal muscle

Cited by 6 publications

References 31 publications

Nanospan, an alternatively spliced isoform of sarcospan, localizes to the sarcoplasmic reticulum in skeletal muscle and is absent in limb girdle muscular dystrophy 2F

Nanospan, an alternatively spliced isoform of sarcospan, localizes to the sarcoplasmic reticulum in skeletal muscle and is absent in limb girdle muscular dystrophy 2F

Altered calcium pump and secondary deficiency of γ-sarcoglycan and microspan in sarcoplasmic reticulum membranes isolated from δ-sarcoglycan knockout mice

Nitrosative stress elicited by nNOSµ delocalization inhibits muscle force in dystrophin‐null mice

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