Biglycan binds to α‐ and γ‐sarcoglycan and regulates their expression during development

Rafii, Michael S.; Hagiwara, Hiroki; Mercado, Mary Lynn T.; Seo, Neung Seon; Xu, T.; Dugan, Tracey A.; Owens, Rick T.; Höök, Magnus; McQuillan, David J.; Young, Marian F.; Fallon, Justin R.

doi:10.1002/jcp.20740

Cited by 54 publications

(47 citation statements)

References 60 publications

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“…2) (15). Furthermore, these proteins as well as β2 syntrophin are dysregulated in bgn −/o mice (14,15). Western blotting of membrane fractions provided further evidence that rhBGN treatment increased the levels of both utrophin and γ-sarcoglycan mdx mice ( Fig.…”

Section: Rhbgn Up-regulates Utrophin and Other Dapc Components In MDXmentioning

confidence: 75%

“…(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%

“…injection. This stable association could be due in part to binding to collagen VI in the ECM (35) and to sarcoglycans at the sarcolemma (14). The longacting properties of systemically delivered rhBGN in mice suggest that this therapeutic strategy could be practical for use in humans, where treatment will likely be required for years.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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.

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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: Rhbgn Up-regulates Utrophin and Other Dapc Components In MDXmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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.

Self Cite

136

103

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show abstract

“…Biglycan binds to components of the dystrophin associated glycoprotein complex, including ␣-dystroglycan, ␣ and ␥ sarcoglycan, as well as collagens I and VI. [95][96][97] It is highly expressed in developing and regenerating muscle. 98 Biglycan null mice exhibit a mild dystrophic phenotype and have reduction in the cytosolic dystrophin associated proteins dystrobrevin, syntrophin and neuronal nitric oxide synthase (nNOS).…”

Section: Emerging Therapeutic Targetsmentioning

confidence: 99%

Approaching a New Age in Duchenne Muscular Dystrophy Treatment

Wagner

2008

Neurotherapeutics

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Summary:Duchenne muscular dystrophy is the most common and severe form of muscular dystrophy. The cornerstones of current treatment include corticosteroids for skeletal muscle weakness, afterload reduction for cardiomyopathy, and noninvasive ventilation for respiratory failure. With these interventions, patients are walking and living longer. However, the current status is still far from adequate. Increased private and federal funding of studies in Duchenne muscular dystrophy has led to a large number of novel agents with propitious therapeutic potential. These include agents that modify dystrophin expression, increase muscle growth and regeneration, and modulate inflammatory responses. Many of these agents are already in clinical trials. Challenges to the development of additional novel therapeutics exist, including lack of validated animal models and lack of adequate biomarkers as surrogate endpoints. However, these challenges are not insurmountable and the next decade will likely see meaningful, new treatment options introduced into the clinical care of patients with Duchenne muscular dystrophy.

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Transcriptome analysis of collagen VI‐related muscular dystrophy muscle biopsies

Guadagnin

Mohassel

Johnson

et al. 2021

Ann Clin Transl Neurol

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Objective: To define the transcriptomic changes responsible for the histologic alterations in skeletal muscle and their progression in collagen VI-related muscular dystrophy (COL6-RD). Methods: COL6-RD patient muscle biopsies were stratified into three groups based on the overall level of pathologic severity considering degrees of fibrosis, muscle fiber atrophy, and fatty replacement of muscle tissue. Using microarray and RNA-Seq, we then performed global gene expression profiling on the same muscle biopsies and compared their transcriptome with age-and sex-matched controls. Results: COL6-RD muscle biopsy transcriptomes as a group revealed prominent upregulation of muscle extracellular matrix component genes and the downregulation of skeletal muscle and mitochondrion-specific genes. Upregulation of the TGFb pathway was the most conspicuous change across all biopsies and was fully evident even in the mildest/earliest histological group. There was no difference in the overall transcriptional signature between the different histologic groups but polyserial analysis identified relative changes along with COL6-RD histological severity. Interpretation: Overall, our study establishes the prominent dysregulation of extracellular matrix genes, TGFb signaling, and its downstream cellular pathways at the transcriptomic level in COL6-RD muscle.

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Biglycan binds to α‐ and γ‐sarcoglycan and regulates their expression during development

Cited by 54 publications

References 60 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

Approaching a New Age in Duchenne Muscular Dystrophy Treatment

Transcriptome analysis of collagen VI‐related muscular dystrophy muscle biopsies

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