Dystrophin and utrophin expression require sarcospan: loss of α7 integrin exacerbates a newly discovered muscle phenotype in sarcospan-null mice

Marshall, Jamie L.; Chou, Eric; Oh, Jonghyun; Kwok, Allan M. F.; Burkin, Dean J.; Crosbie-Watson, Rachelle H.

doi:10.1093/hmg/dds271

Cited by 44 publications

(88 citation statements)

References 77 publications

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“…The tetraspanins CD9, CD81 and CD53 have each been implicated in muscle cell fusion (Tachibana and Hemler, 1999; Liu et al, 2012). Transgenic overexpression of sarcospan, a tetraspanin associated with the DAPC, leads to dystrophic sarcolemma stabilization through upregulation of utrophin and activation of AKT signaling (Marshall et al, 2012; Marshall et al, 2013). CD82 has been mostly studied in cancer, as its expression is associated with inhibition of metastasis formation (Dong et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

CD82 Is a Marker for Prospective Isolation of Human Muscle Satellite Cells and Is Linked to Muscular Dystrophies

et al. 2016

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Summary Cell surface markers for prospective isolation of stem cells from human skeletal muscle have been difficult to identify. Such markers would be powerful tools for studying satellite cell function during homeostasis and in pathogenesis of diseases such as muscular dystrophies. In this study, we show that the tetraspanin KAI/CD82 is an excellent marker for prospectively isolating stem cells from human fetal and adult skeletal muscle. Human CD82+ muscle cells robustly engraft into a mouse model of muscular dystrophy. shRNA knockdown of CD82 in myogenic cells reduces myoblast proliferation, suggesting it is functionally involved in muscle homeostasis. CD82 physically interacts with alpha7beta1 integrin (α7β1-ITG) and with α-sarcoglycan, a member of the Dystrophin-Associated Glycoprotein Complex (DAPC), both of which have been linked to muscular dystrophies. Consistently, CD82 expression is decreased in Duchenne muscular dystrophy patients, together suggesting that CD82 function may be important for muscle stem cell function in muscular disorders.

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Section: Discussionmentioning

confidence: 99%

CD82 Is a Marker for Prospective Isolation of Human Muscle Satellite Cells and Is Linked to Muscular Dystrophies

et al. 2016

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“…The role of sarcospan has been more clearly delineated using mice engineered to lack sarcospan (102). The myopathy present in sarcospan null mice is mild but is exacerbated by loss of α7-integrin (107). Sarcospan is a member of the tetraspanin family that is known to interact with integrins (12, 44)…”

Section: The Dystrophin Complexmentioning

confidence: 99%

The Dystrophin Complex: Structure, Function, and Implications for Therapy

Gao

McNally

2015

Comprehensive Physiology

358

309

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The dystrophin complex stabilizes the plasma membrane of striated muscle cells. Loss of function mutations in the genes encoding dystrophin, or the associated proteins, triggers instability of the plasma membrane and myofiber loss. Mutations in dystrophin have been extensively cataloged providing remarkable structure-function correlation between predicted protein structure and clinical outcomes. These data have highlighted dystrophin regions necessary for in vivo function and fueled the design of viral vectors and now, exon skipping approaches for use in dystrophin restoration therapies. However, dystrophin restoration is likely more complex, owing to the role of the dystrophin complex as a broad cytoskeletal integrator. This review will focus on dystrophin restoration, with emphasis on the regions of dystrophin essential for interacting with its associated proteins and discuss the structural implications of these approaches.

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“…Only proteins that bind with high affinity and specificity will be retained with dystrophin during sucrose gradient fractionation where it migrates as an 18S complex [2-4,12]. SSPN co-migrates with peak DGC-containing fractions providing additional evidence that SSPN is an integral component of the DGC [5,7,13,14]. In contrast, while a fraction of caveolin-3 maintains association with the DGC during purification by sWGA lectin affinity chromatography, it is localized to heavier fractions during sucrose gradient centrifugation [7,13].…”

Section: Reviewmentioning

confidence: 99%

“…However, when SSPN-null mice were analyzed at older ages (4.5 month old), several deficiencies emerged. Reduction in the levels of the UGC and DGC as well as diminished NMJ-specific glycosylation of α-DG and decreased laminin-binding was observed in aged SSPN-nulls [14]. Diaphragms from older SSPN-null mice exhibited diminished specific force generating capacity and were more susceptible to eccentric-contraction induced damage as evidenced by the increased percentage drop in force compared to wild-type controls [14].…”

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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Dystrophin and utrophin expression require sarcospan: loss of α7 integrin exacerbates a newly discovered muscle phenotype in sarcospan-null mice

Cited by 44 publications

References 77 publications

CD82 Is a Marker for Prospective Isolation of Human Muscle Satellite Cells and Is Linked to Muscular Dystrophies

CD82 Is a Marker for Prospective Isolation of Human Muscle Satellite Cells and Is Linked to Muscular Dystrophies

The Dystrophin Complex: Structure, Function, and Implications for Therapy

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

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