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

Solares-Pérez, Alhondra; Álvarez, Rocío; Crosbie, Rachelle H.; Vega-Moreno, Jesús; Medina-Monares, Joel; Estrada-Mena, Francisco Javier; Ortega, Alejandro López; Coral‐Vázquez, Ramón Mauricio

doi:10.1016/j.ceca.2010.06.003

Cited by 10 publications

(17 citation statements)

References 46 publications

(58 reference statements)

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“…A comparable fatigue protocol in EDL muscle obtained from mice with muscular dystrophy resulted in irreversible damage [5,18]. In cholesterol-depleted muscle, the observed immediate mechanical recovery of the EDL muscle after cholesterol restoration suggested that the interaction of membrane proteins with the sub-sarcolemmal cytoskeleton is strongly dependent on the sarcolemmal cholesterol concentration.…”

Section: Effect Of Mβcd On Muscle Fatigue By a Train Of Single Twitchmentioning

confidence: 85%

“…Sarcoglycanopathies are a group of four autosomal recessive limb girdle muscular dystrophies (LGMDs) caused by mutations of the α, β, γ and δ sarcoglycan genes, resulting in the disruption of the sarcomeric arrangement of the SGC in the sarcolemma [17] and sarcoplasmic reticulum (SR) [18]. Some naturally occurring mutations in the DG gene have been associated with specific types of muscular dystrophy [19], but the absence of β-DG in skeletal muscle is embryonically lethal [20].…”

Section: Introductionmentioning

confidence: 99%

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Cholesterol Depletion Uncouples �-dystroglycans from Discrete Sarcolemmal Domains, Reducing the Mechanical Activity of Skeletal Muscle

Vega-Moreno

Tirado-Cortés²,

Álvarez³

et al. 2012

Cell Physiol Biochem

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Background/Aims: β-Dystroglycan (β-DG) is a transmembrane glycoprotein that links the intracellular cytoskeleton to the extracellular matrix and is crucial for the molecular pathway of lateral force transmission in muscle. We aimed to investigate the effect of decreasing sarcolemmal cholesterol on the distribution of β-DG, its interaction with dystrophin and the impact on the contraction efficiency of muscle. Methods: Isolated rat extensor digitorum longus muscles were incubated with methyl β-cyclodextrin (MβCD) to deplete cholesterol and with MβCD-cholesterol to restore cholesterol. Electric stimulation protocols were used to determine muscle force and fatigue. Detergent-resistant membranes (lipid rafts) were separated from isolated skeletal muscle sarcolemma. The distribution and interactions of β-DG, caveolin-3 and dystrophin were determined by an immunoreactivity analysis. Results: Cholesterol depletion in muscle results in a weakened force of contraction, which recovers after cholesterol restoration. The rate of fatigue is unaffected, but fatigue recovery is dependent upon cholesterol restoration. MβCD modifies the structures of lipid rafts obtained from MβCD-treated muscles by, displacing the membrane proteins β-DG and caveolin-3 f from the lipid raft, thus reducing the interaction of β-DG with dystrophin. Conclusion: Cholesterol depletion weakens the muscle contractile force by disturbing the sarcolemmal distribution of β-dystroglycan and its interaction with dystrophin, two key proteins in the alignment of lateral force transmission pathway.

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Section: Effect Of Mβcd On Muscle Fatigue By a Train Of Single Twitchmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Cholesterol Depletion Uncouples �-dystroglycans from Discrete Sarcolemmal Domains, Reducing the Mechanical Activity of Skeletal Muscle

Vega-Moreno

Tirado-Cortés²,

Álvarez³

et al. 2012

Cell Physiol Biochem

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“…Overexpression of μSPN in skeletal muscle of transgenic mice reduces levels of ryanodine receptor, dihydropyridine receptor as well as SERCA-1 resulting in aberrant triad morphology [10]. μSPN is also reduced in isolated SR membranes of δ-SG-null muscle contributing to SERCA dysfunction [110]. Given that both SSPN and μSPN interact with proteins that are critical to skeletal muscle function, it can be hypothesized that genetic mutations affecting SSPN function would have significant consequences for muscle.…”

Section: Reviewmentioning

confidence: 99%

Sarcospan: a small protein with large potential for Duchenne muscular dystrophy

Marshall

Crosbie-Watson

2013

Skeletal Muscle

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Purification of the proteins associated with dystrophin, the gene product responsible for Duchenne muscular dystrophy, led to the discovery of the dystrophin-glycoprotein complex. Sarcospan, a 25-kDa transmembrane protein, was the last component to be identified and its function in skeletal muscle has been elusive. This review will focus on progress over the last decade revealing that sarcospan is an important regulator of muscle cell adhesion, strength, and regeneration. Investigations using several transgenic mouse models demonstrate that overexpression of sarcospan in the mouse model for Duchenne muscular dystrophy ameliorates pathology and restores muscle cell binding to laminin. Sarcospan improves cell surface expression of the dystrophin- and utrophin-glycoprotein complexes as well as α7β1 integrin, which are the three major laminin-binding complexes in muscle. Utrophin and α7β1 integrin compensate for the loss of dystrophin and the finding that sarcospan increases their abundance at the extra-synaptic sarcolemma supports the use of sarcospan as a therapeutic target. Newly discovered phenotypes in sarcospan-deficient mice, including a reduction in specific force output and increased drop in force in the diaphragm muscle, result from decreased utrophin and dystrophin expression and further reveal sarcospan’s role in determining abundance of these complexes. Dystrophin protein levels and the specific force output of the diaphragm muscle are further reduced upon genetic removal of α7 integrin (Itga7) in SSPN-deficient mice, demonstrating that interactions between integrin and sarcospan are critical for maintenance of the dystrophin-glycoprotein complex and force production of the diaphragm muscle. Sarcospan is a major regulator of Akt signaling pathways and sarcospan-deficiency significantly impairs muscle regeneration, a process that is dependent on Akt activation. Intriguingly, sarcospan regulates glycosylation of a specific subpopulation of α-dystroglycan, the laminin-binding receptor associated with dystrophin and utrophin, localized to the neuromuscular junction. Understanding the basic mechanisms responsible for assembly and trafficking of the dystrophin- and utrophin-glycoprotein complexes to the cell surface is lacking and recent studies suggest that sarcospan plays a role in these essential processes.

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“…We have previously identified an alternatively spliced isoform of SSPN that is not localized to the sarcolemma [ 25 ]. SSPN messenger RNA (mRNA) undergoes alternative splicing to generate a novel smaller protein that we named microspan (μSPN) [ 25 ], which is enriched in both the light and heavy fractions of the SR membrane (LSR and HSR, respectively) [ 26 ]. Analysis of the SR fractions revealed that while γ-SG, δ-SG, δ-SG3, and μSPN are all present in the LSR, only δ-SG3 and μSPN seem to be expressed in the HSR.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, evaluation of the expression of these proteins in skeletal muscle of Sgcd −/− mice showed that loss of δ-SG expression results in secondary loss of γ-SG and μSPN. The findings raise the possibility that these proteins may be associated as a complex in the SR membranes and that δ-SG (or δ-SG3) may play a role in the stabilization and/or localization of γ-SG and μSPN expression at the SR [ 26 ]. Assessment of the Ca 2+ release and uptake of the LSR and HSR from wild-type and Sgcd −/− mice showed that, whereas the Ca 2+ release from HSR vesicles from these mice is not different, Ca 2+ efflux (mainly through SERCA1) is considerably increased in LSR vesicles from Sgcd −/− mice [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

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

Cited by 10 publications

References 46 publications

Cholesterol Depletion Uncouples �-dystroglycans from Discrete Sarcolemmal Domains, Reducing the Mechanical Activity of Skeletal Muscle

Cholesterol Depletion Uncouples �-dystroglycans from Discrete Sarcolemmal Domains, Reducing the Mechanical Activity of Skeletal Muscle

Sarcospan: a small protein with large potential for Duchenne muscular dystrophy

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

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