Biglycan regulates the expression and sarcolemmal localization of dystrobrevin, syntrophin, and nNOS

Mercado, Mary Lynn T.; Amenta, Alison R.; Hagiwara, Hiroki; Rafii, Michael S.; Lechner, Beatrice E.; Owens, Rick T.; McQuillan, David J.; Froehner, Stanley C.; Fallon, Justin R.

doi:10.1096/fj.05-5124fje

Cited by 56 publications

(61 citation statements)

References 35 publications

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“…These observations indicate that the circulating recombinant protein partitions to muscle where it becomes stably associated with the ECM. This result is in agreement with our earlier findings that intramuscularly delivered rhBGN is stable in muscle for at least 2 wk following a single intramuscular injection in bgn −/o mice (15). This finding is also consistent with the efficacy of rhBGN observed 2 wk after a single injection in mdx mice (discussed below).…”

Section: Endogenous Biglycan Regulates Utrophin Expression In Immaturesupporting

confidence: 93%

“…The role for biglycan in recruiting utrophin to the membrane, taken together with previous results, showing that both endogenous biglycan and intramuscularly delivered rhBGN can regulate DAPC proteins in vivo (15), raising the possibility that rhBGN could be a therapeutic agent for DMD. As a first step toward developing such a therapy, we asked whether rhBGN could be delivered systemically.…”

Section: Endogenous Biglycan Regulates Utrophin Expression In Immaturementioning

confidence: 62%

“…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%

“…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.…”

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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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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: Endogenous Biglycan Regulates Utrophin Expression In Immaturesupporting

confidence: 93%

Section: Endogenous Biglycan Regulates Utrophin Expression In Immaturementioning

confidence: 62%

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

confidence: 75%

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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“…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). 99 Remarkably, recombinant biglycan can be injected into muscle, become stably associated with the sarcolemma and extracellular matrix, and restore expression of cytosolic dystrophin associated proteins to the plasma membrane in null mice. 99 Studies evaluating the effects of biglycan to ameliorate dystrophic features in the absence of dystrophin will be extremely interesting and potentially warrant pharmacologic development for clinical trials in DMD.…”

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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ECM‐Related Myopathies and Muscular Dystrophies: Pros and Cons of Protein Therapies

Fontelonga

Barraza-Flores

et al. 2017

Comprehensive Physiology

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Extracellular matrix (ECM) myopathies and muscular dystrophies are a group of genetic diseases caused by mutations in genes encoding proteins that provide critical links between muscle cells and the extracellular matrix. These include structural proteins of the ECM, muscle cell receptors, enzymes, and intracellular proteins. Loss of adhesion within the myomatrix results in progressive muscle weakness. For many ECM muscular dystrophies, symptoms can occur any time after birth and often result in reduced life expectancy. There are no cures for the ECM-related muscular dystrophies and treatment options are limited to palliative care. Several therapeutic approaches have been explored to treat muscular dystrophies including gene therapy, gene editing, exon skipping, embryonic, and adult stem cell therapy, targeting genetic modifiers, modulating inflammatory responses, or preventing muscle degeneration. Recently, protein therapies that replace components of the defective myomatrix or enhance muscle and/or extracellular matrix integrity and function have been explored. Preclinical studies for many of these biologics have been promising in animal models of these muscle diseases. This review aims to summarize the ECM muscular dystrophies for which protein therapies are being developed and discuss the exciting potential and possible limitations of this approach for treating this family of devastating genetic muscle diseases. © 2017 American Physiological Society. Compr Physiol 7:1519-1536, 2017.

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Biglycan regulates the expression and sarcolemmal localization of dystrobrevin, syntrophin, and nNOS

Cited by 56 publications

References 35 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

ECM‐Related Myopathies and Muscular Dystrophies: Pros and Cons of Protein Therapies

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