Sarcoglycan Subcomplex Expression in Normal Human Smooth Muscle

Anastasi, Giuseppe; Cutroneo, Giuseppina; Sidoti, Antonina; Rinaldi, Carmen; Bruschetta, Daniele; Rizzo, Giuseppina; D’Angelo, Rosalia; Tarone, Guido; Amato, Aldo; Favaloro, Angelo

doi:10.1369/jhc.6a7145.2007

Cited by 26 publications

(32 citation statements)

References 39 publications

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“…(iv) RhBGN restores the expression of DAPC components that are important for muscle integrity and function. (v) RhBGN could selectively target the tissues affected in DMD, as it binds to α-and γ-sarcoglycan (14), which are components of the dystrophin/ utrophin protein complex and are expressed selectively in heart and skeletal muscle (29)(30)(31)(32). (vi) RhBGN is well tolerated in mdx mice.…”

Section: Discussionmentioning

confidence: 99%

Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice

Amenta¹,

Yilmaz

Bogdanovich

et al. 2010

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

136

103

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Duchenne muscular dystrophy (DMD) is caused by mutations in dystrophin and the subsequent disruption of the dystrophin-associated protein complex (DAPC). Utrophin is a dystrophin homolog expressed at high levels in developing muscle that is an attractive target for DMD therapy. Here we show that the extracellular matrix protein biglycan regulates utrophin expression in immature muscle and that recombinant human biglycan (rhBGN) increases utrophin expression in cultured myotubes. Systemically delivered rhBGN upregulates utrophin at the sarcolemma and reduces muscle pathology in the mdx mouse model of DMD. RhBGN treatment also improves muscle function as judged by reduced susceptibility to eccentric contraction-induced injury. Utrophin is required for the rhBGN therapeutic effect. Several lines of evidence indicate that biglycan acts by recruiting utrophin protein to the muscle membrane. RhBGN is well tolerated in animals dosed for as long as 3 months. We propose that rhBGN could be a therapy for DMD.biotherapeutics | protein therapeutics D uchenne muscular dystrophy (DMD) is a hereditary disease that affects ∼1:3,500 boys, the majority of whom will die by their midtwenties (1). DMD is caused by mutations in dystrophin that result in the faulty assembly and function of an ensemble of structural and signaling molecules at the muscle cell surface termed the dystrophin-associated protein complex (DAPC) (2-4). There are currently no treatments that target the primary pathology of DMD.One attractive therapeutic approach for DMD is the stabilization of the muscle cell membrane through up-regulation of utrophin, a dystrophin homolog. Transgenic overexpression of utrophin rescues dystrophic pathology and restores function in the dystrophin-deficient mdx mouse (5-7). In mature muscle, utrophin expression is restricted to the neuromuscular and myotendinous junctions. However, utrophin is expressed over the entire myofiber in developing and regenerating muscle (8-10). These observations raise the possibility that marshalling pathways that normally regulate utrophin expression in developing muscle could be a productive approach for developing DMD treatments.The extracellular matrix protein biglycan plays an important role in developing muscle. In both humans and mice, biglycan is most highly expressed in immature and regenerating muscle (11,12). Biglycan is a component of the DAPC, where it binds to α-dystroglycan (13) and α-and γ-sarcoglycan (14). Biglycan regulates the expression of the sarcoglycans as well as dystrobrevins, syntrophins, and nNOS, particularly in immature muscle. Finally, biglycan is important for timely muscle regeneration (11).Locally delivered recombinant human biglycan (rhBGN) incorporates into the extracellular matrix of bgn −/o muscle where it persists for at least 2 wk and rescues the expression of several DAPC components (15). These results raise the possibility that rhBGN might enhance function in muscle that lacks dystrophin. Here we show that utrophin is down-regulated in immature biglycan null (...

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Section: Discussionmentioning

confidence: 99%

Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice

Amenta¹,

Yilmaz

Bogdanovich

et al. 2010

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

136

103

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“…Our previous immunohistochemical and molecular studies on many sites of the human body, demonstrated that all sarcoglycans, with higher or lower expression, are expressed in human smooth muscle fibers hypothesizing the intriguing possibility of the existence of a pentameric arrangement of the SGC. The higher or lower expression of sarcoglycan subunits could be in conformity with the location and function of smooth muscle (14,27).…”

Section: Discussionmentioning

confidence: 84%

“…In the SMC, the dystroglycan complex (DGC) is associated with the sarcoglycan complex (SGC) (5)(6)(7)(8)(9)(10), in order to provide a mechano-signalling connection from the cytoskeleton-toextracellular matrix (ECM) in myocytes (11)(12)(13)(14). SGC plays a key role at the membrane and it is crucial in maintaining sarcolemma viability in muscle fiber membrane (12).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, SGC may be important in maintaining proper calcium ion balance or may support the development and maintenance of muscle cells through signaling functions (15). The SGC consists of five transmembrane proteins: ·-SG, type-1 transmembrane protein, with amino-terminus on the intracellular face of muscle cells specifically expressed in skeletal and cardiac muscle; ß-SG, a type-2 transmembrane protein that is abundant in cardiac and skeletal muscle; Á-and ‰-SG, also type-2 glycosylated transmembrane protein, highly similar among themselves and to ß-SG (14); ε-SG, homologous to ·-SG, a single-pass type I transmembrane protein with a short cytoplasmic tail containing three putative protein kinase phosphorylation site (16), associated with ß-and ‰-SG in SMC (14).…”

Section: Introductionmentioning

confidence: 99%

“…It is reported that the integrity of SG complex seems to be essential for the viability of smooth muscle (11,14), so that the sarcoglycan subunity mutations or loss is accompanied by pathology (17)(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

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Abnormal distribution of sarcoglycan subcomplex in colonic smooth muscle cells of aganglionic bowel

Favaloro¹

2010

Int J Mol Med

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Abstract. Hirschsprung's disease (HD) is a development disorder of the enteric nervous system in which the altered innervation explains the inability of the aganglionic segment to relax. Impairment of cytoskeleton in SMC of aganglionic bowel has been shown. Sarcoglycan subcomplex (SG) may support the development and maintenance of muscle cells. We examined the SG subunit expression in colonic aganglionic and ganglionic specimens obtained from patients with HD. Full-thickness bowel specimens were obtained from six patients with HD. Six normal colon specimens were used as controls. Immunofluorescent analysis and reverse transcriptase polymerase chain reaction evaluation were performed for ·-, ß-, Á-, ‰-and ε-SG. In control colon, the indirect immunofluorescence showed a strong staining pattern of ß-Á-‰-and ε-SG while a weak positivity of ·-SG was recorded. In aganglionic bowel, immunofluorescence intensity values documented a significant lack of ε-SG while an enhanced ·-SG, coupled to a loss of ε-SG, was recorded in ganglionic bowel in HD-affected patients. Our observations underscore the assumption that non-neuronal elements of the colon might play a key role in the pathogenesis of HD and loss of Â-SG might critically alter the cytoskeleton in the aganglionic bowel segment. Up-regulation of ·-SG is probably an acquired phenomenon to reinforce the sarcolemma and to perform a forceful contraction in dilated ganglionic HDaffected colon, related to chronic pseudo-obstruction, contributing to the intestinal dysmotility that persists in 20% of patients after resection of the aganglionic bowel.

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Sarcoglycan Complex in Human Normal and Pathological Prostatic Tissue: An Immunohistochemical and RT‐PCR Study

Cutroneo

Bramantı

Favaloro

et al. 2013

The Anatomical Record

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The sarcoglycan complex is a trans-membrane system playing a key role in mechano-signaling the connection from the cytoskeleton to the extracellular matrix. While b-, d-, and e-sarcoglycans are widely distributed, g-and a-sarcoglycans are expressed exclusively in skeletal and cardiac muscle. Insufficient data are available on the distribution of sarcoglycans in nonmuscular tissue. In the present study, we used immunohistochemical and RT-PCR techniques to study the sarcoglycans also in normal human glandular tissue, a type of tissue never studied in relation to the sarcoglycan complex, with the aim of verifying the real wider distribution of this complex. To understand the role of sarcoglycans, we tested specimens collected from patients affected by benign prostatic hyperplasia and adenocarcinoma. For the first time, our results showed that all sarcoglycans are detectable in normal samples both in epithelial and in myoepithelial cells; in pathological prostate, sarcoglycans appeared severely reduced in number or were absent. These data demonstrated that all sarcoglycans have a wider distribution suggesting a new unknown role for these proteins. The decreased number of sarcoglycans, containing cadherin domain homologs in samples of prostate affected by hyperplasia, and the absence of proteins in prostate biopsies, in cases affected by adenocarcinoma, could be responsible for the loss of adhesion between epithelial cells, which in turn facilitates the progression of benign tumors and the invasive potential of malignant tumors. Anat Rec,

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Sarcoglycan Subcomplex Expression in Normal Human Smooth Muscle

Cited by 26 publications

References 39 publications

Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice

Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice

Abnormal distribution of sarcoglycan subcomplex in colonic smooth muscle cells of aganglionic bowel

Sarcoglycan Complex in Human Normal and Pathological Prostatic Tissue: An Immunohistochemical and RT‐PCR Study

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