Sarcospan-Deficient Mice Maintain Normal Muscle Function

Lebakken, Connie S.; Venzke, David; Hrstka, Ronald F.; Consolino, Christina M.; Faulkner, John A.; Williamson, Roger A.; Campbell, Kevin P.

doi:10.1128/mcb.20.5.1669-1677.2000

Cited by 63 publications

(73 citation statements)

References 74 publications

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“…SSPN-deficient mice maintain normal muscle function and do not exhibit perturbation of the DGC (Lebakken et al, 2000). One possible conclusion from this work might be that SSPN is not a critical component of the DGC and does not contribute to muscle function.…”

Section: Introductionmentioning

confidence: 81%

“…Although we propose an important role for SSPN within the DGC, data from the SSPN-deficient mice (Lebakken et al, 2000) has not provided much insight into SSPN's function. SSPN-null mice exhibit wild-type levels of DGC protein expression and possess normal force and power generation capabilities (Lebakken et al, 2000). It is feasible that SSPN is replaced by a functionally similar tetraspanin during muscle development, which does not clarify the interpretation of SSPN's role in muscle physiology.…”

Section: Discussionmentioning

confidence: 99%

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Disrupted mechanical stability of the dystrophin-glycoprotein complex causes severe muscular dystrophy in sarcospan transgenic mice

Peter

Miller

Crosbie

2007

Journal of Cell Science

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The dystrophin-glycoprotein complex spans the muscle plasma membrane and provides a mechanical linkage between laminin in the extracellular matrix and actin in the intracellular cytoskeleton. Within the dystrophin-glycoprotein complex, the sarcoglycans and sarcospan constitute a subcomplex of transmembrane proteins that stabilize α-dystroglycan, a receptor for laminin and other components of the extracellular matrix. In order to elucidate the function of sarcospan, we generated transgenic mice that overexpress sarcospan in skeletal muscle. Sarcospan transgenic mice with moderate (tenfold) levels of sarcospan overexpression exhibit a severe phenotype that is similar to mouse models of laminin-deficient congenital muscular dystrophy (MD). Sarcospan transgenic mice display severe kyphosis and die prematurely between 6 and 10 weeks of age. Histological analysis reveals that sarcospan expression causes muscle pathology marked by increased muscle fiber degeneration and/or regeneration. Sarcospan transgenic muscle does not display sarcolemma damage, which is distinct from dystrophin- and sarcoglycan-deficient muscular dystrophies. We show that sarcospan clusters the sarcoglycans into insoluble protein aggregates and causes destabilization of α-dystroglycan. Evidence is provided to demonstrate abnormal extracellular matrix assembly, which represents a probable pathological mechanism for the severe and lethal dystrophic phenotype. Taken together, these data suggest that sarcospan plays an important mechanical role in stabilizing the dystrophin-glycoprotein complex.

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Section: Introductionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Disrupted mechanical stability of the dystrophin-glycoprotein complex causes severe muscular dystrophy in sarcospan transgenic mice

Peter

Miller

Crosbie

2007

Journal of Cell Science

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“…Antibodies-Mouse monoclonal antibodies Ad1/20A6 against ␣-sarcoglycan, ␤Sarc1/5B1 against ␤-sarcoglycan, and 35DAG/21B5 against ␥-sarcoglycan were generated in collaboration with Louise V. B. , and utrophin (Rabbit 56) were described previously (24,37,40,(42)(43)(44)(45). A commercial monoclonal antibody (clone 1A4, Sigma) was used to detect smooth muscle ␣-actin.…”

Section: Methodsmentioning

confidence: 99%

Expression of γ-Sarcoglycan in Smooth Muscle and Its Interaction with the Smooth Muscle Sarcoglycan-Sarcospan Complex

Barresi¹,

Moore²,

Stolle³

et al. 2000

Journal of Biological Chemistry

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The sarcoglycan complex in striated muscle is a heterotetrameric unit integrally associated with sarcospan in the dystrophin-glycoprotein complex. The sarcoglycans, ␣, ␤, ␥, and ␦, are mutually dependent with regard to their localization at the sarcolemma, and mutations in any of the sarcoglycan genes lead to limb-girdle muscular dystrophies type 2C-2F. In smooth muscle ␤-and ␦-sarcoglycans are associated with ⑀-sarcoglycan, a glycoprotein homologous to ␣-sarcoglycan. Here, we demonstrate that ␥-sarcoglycan is also a component of the sarcoglycan complex in the smooth muscle. First, we show the presence of ␥-sarcoglycan in a number of smooth muscle-containing organs, and we verify the existence of identical transcripts in skeletal and smooth muscle. The specificity of the expression of ␥-sarcoglycan in smooth muscle was confirmed by analysis of smooth muscle cells in culture. Next, we provide evidence for the association of ␥-sarcoglycan with the sarcoglycan-sarcospan complex by biochemical analysis and comparison among animal models for muscular dystrophy. Moreover, we find disruption of the sarcoglycan complex in the vascular smooth muscle of a patient with ␥-sarcoglycanopathy. Taken together, our results prove that the sarcoglycan complex in vascular and visceral smooth muscle consists of ⑀-, ␤-, ␥-, and ␦-sarcoglycans and is associated with sarcospan.The sarcoglycan-sarcospan complex (SGC) 1 is part of the dystrophin-glycoprotein complex (DGC), a group of proteins well characterized in skeletal and cardiac muscle. The DGC also includes dystrophin, dystroglycan (␣-and ␤-), and syntrophins (for reviews see Refs. 1-4). Recently, other proteins such as dystrobrevin (5-7) and neuronal nitric-oxide synthase (8 -10) have been shown to correlate with the DGC at the sarcolemma. The interaction of the DGC with components of the extracellular matrix (11-13) may have an important role in force transmission and in sarcolemmal protection (14 -16). The importance of the SGC in maintaining the sarcolemmal stability is evident from the various forms of limb-girdle muscular dystrophy (LGMD) caused by mutations in any of the genes coding for the SGs (17-21). In addition, a functional role for the SGC in signaling has been hypothesized (22,23).Several mouse models of muscular dystrophy have been engineered in which ␣-(Sgca-null) (24, 25), ␤-(Sgcb-null) (26, 27), ␥-(Sgcg-null) (28), or ␦-SG (Sgcd-null) (29, 30) genes have been disrupted. In addition to the skeletal muscle pathology, all but the Sgca-null mice show a cardiomyopathic phenotype. Furthermore, a spontaneous mutant, the ␦-SG-deficient BIO14.6 hamster, has been studied as an animal model for dilated and hypertrophic cardiomyopathy (31, 32). Correspondingly, patients with defects in ␤-, ␥-, and ␦-SGs, but not ␣-SG, are occasionally affected by dilated cardiomyopathy (33)(34)(35).In skeletal and cardiac muscle, the SGC is a heterotetrameric unit composed of the transmembrane glycoproteins ␣-, ␤-, ␥-, and ␦-SGs. The synthesis of all four of the proteins is required in or...

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“…Glycoprotein preparations were performed as described (12) and analyzed by using Abs against ␣-SG (␣Sarc͞20A6); ␤-SG (␤Sarc͞5B1); ␣-dystroglycan (IIH6) (20); ␣2 subunit of the dihydropyridine receptor (21); ␦-SG (14) and sarcospan (18).…”

Section: Animalsmentioning

confidence: 99%

“…Stainings were performed as described (12) with Abs against ␤-dystroglycan (15); ␣-, ␤-, ␥-, and ␦-SG (8,14,16,17); sarcospan (18), and neuronal nitric oxide synthase (nNOS) (19). The smooth muscle actin Ab was from Sigma.…”

Section: Animalsmentioning

confidence: 99%

Gene transfer establishes primacy of striated vs. smooth muscle sarcoglycan complex in limb-girdle muscular dystrophy

Durbeej

Sawatzki

Barresi

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Limb-girdle muscular dystrophy types 2E and F are characterized by skeletal muscle weakness and often cardiomyopathy and are due to mutations in the genes encoding ␤-and ␦-sarcoglycan. We previously demonstrated that loss of sarcoglycans in smooth muscle leads to constrictions of the microvasculature that contributes to the cardiac phenotype. It is unclear how vasculature abnormalities affect skeletal muscle. We injected recombinant ␤-or ␦-sarcoglycan adenoviruses into skeletal muscles of corresponding null mice. We hypothesized that the adenoviruses would not transduce vascular smooth muscle, and we would only target skeletal muscle. Indeed, sustained expression of intact sarcoglycansarcospan complex was noted at the sarcolemma, neuromuscular junction, myotendinous junction, and in peripheral nerve, but not in vascular smooth muscle. Gene transfer of the corresponding deleted sarcoglycan gene preserved sarcolemmal integrity, prevented pathological dystrophy and hypertrophy, and protected against exercised-induced damage. We conclude that vascular dysfunction is not a primary cause of ␤-and ␦-sarcoglycan-deficient muscular dystrophy. In addition, we show successful functional rescue of entire muscles after adenovirus-mediated gene delivery. Thus, virus-mediated gene transfer of sarcoglycans to skeletal muscle in combination with pharmacological prevention of cardiomyopathy constitute promising therapeutic strategies for limb-girdle muscular dystrophies.

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Sarcospan-Deficient Mice Maintain Normal Muscle Function

Cited by 63 publications

References 74 publications

Disrupted mechanical stability of the dystrophin-glycoprotein complex causes severe muscular dystrophy in sarcospan transgenic mice

Disrupted mechanical stability of the dystrophin-glycoprotein complex causes severe muscular dystrophy in sarcospan transgenic mice

Expression of γ-Sarcoglycan in Smooth Muscle and Its Interaction with the Smooth Muscle Sarcoglycan-Sarcospan Complex

Gene transfer establishes primacy of striated vs. smooth muscle sarcoglycan complex in limb-girdle muscular dystrophy

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