Overexpression of mini‐agrin in skeletal muscle increases muscle integrity and regenerative capacity in laminin‐α2‐deficient mice

Bentzinger, C. Florian; Barzaghi, Patrizia; Lin, Shuo; Rüegg, Markus A.

doi:10.1096/fj.04-3376com

Cited by 96 publications

(97 citation statements)

References 32 publications

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“…Feret's breadth gives the most accurate measurement of fiber size, being unaffected if fiber orientation is not in complete cross-sectional orientation (Briguet et al, 2004). Feret's Breadth is described as "the minimum distance of parallel tangents at opposing particle borders" (Bentzinger et al, 2005), a feature that the QWin v3.1 image analysis software uses to generate the minimal Feret's diameter for each fiber. The percentage of regenerated (as determined by the presence of nonperipheral nuclei), nonregenerated, and calcified fibers was determined for each field.…”

Section: Analysis Of Muscle Fibersmentioning

confidence: 99%

Lack of galectin‐1 results in defects in myoblast fusion and muscle regeneration

Georgiadis

Stewart

Pollard

et al. 2007

Developmental Dynamics

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Galectin-1 has been implicated in the development of skeletal muscle, being maximally expressed at the time of myofiber formation. Furthermore, in the presence of exogenous galectin-1, mononuclear myoblasts show increased fusion in vitro. In the current study, we have used the galectin-1 null mouse to elucidate the role of galectin-1 in skeletal muscle development and regeneration. Myoblasts derived from the galectin-1 mutant showed a reduced ability to fuse in vitro. In galectin-1 null mutants, there was evidence of a delay in muscle fiber development at the neonatal stage and muscle fiber diameter was reduced when compared with wild-type at the adult stage. Muscle regeneration was also compromised in the galectin-1 mutant with the process being delayed and a reduced fiber size being maintained. These results, therefore, show a definitive role for galectin-1 in fusion of myoblasts both in vitro, in vivo, and in regeneration after recovery from induced injury. Developmental Dynamics 236:1014 -1024, 2007.

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Section: Analysis Of Muscle Fibersmentioning

confidence: 99%

Lack of galectin‐1 results in defects in myoblast fusion and muscle regeneration

Georgiadis

Stewart

Pollard

et al. 2007

Developmental Dynamics

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“…The dy W /dy W mouse model (Kuang et al, 1998) of MDC1A largely recapitulates the human disease. It is characterized by a severe degeneration and incomplete regeneration of damaged muscle fibers (Miyagoe et al, 1997;Kuang et al, 1999;Bentzinger et al, 2005;Meinen et al, 2007). Histology of affected muscles typically shows variation in muscle fiber size, extensive fibrosis, infiltration of adipose tissue, and high levels of creatine kinase (CK) in the blood.…”

mentioning

confidence: 99%

“…Finally, like human patients, these mice die prematurely. Apoptosis has been reported as a pathological hallmark at the cellular level of affected muscle tissue both in dy W /dy W mice (Kuang et al, 1999;Girgenrath et al, 2004;Bentzinger et al, 2005;Dominov et al, 2005) and MDC1A patients (Hayashi et al, 2001).…”

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confidence: 99%

Omigapil Ameliorates the Pathology of Muscle Dystrophy Caused by Laminin-α2 Deficiency

Erb

Meinen²,

Barzaghi³

et al. 2009

J Pharmacol Exp Ther

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Laminin ␣2-deficient congenital muscular dystrophy, called MDC1A, is a rare, devastating genetic disease characterized by severe neonatal hypotonia ("floppy infant syndrome"), peripheral neuropathy, inability to stand or walk, respiratory distress, and premature death in early life. Transgenic overexpression of the apoptosis inhibitor protein BCL-2, or deletion of the proapoptotic Bax gene in a mouse model for MDC1A prolongs survival and mitigates pathology, indicating that apoptotic events are involved in the pathology. Here we demonstrate that the proapoptotic glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-Siah1-CBP/p300-p53 pathway is activated in a mouse model for MDC1A. Moreover, we show that omigapil, which inhibits GAPDH-Siah1-mediated apoptosis, ameliorates several pathological hallmarks in the MDC1A mouse model. Specifically, we demonstrate that treatment with omigapil inhibits apoptosis in muscle, reduces body weight loss and skeletal deformation, increases locomotive activity, and protects from early mortality. These data qualify omigapil, which is in late phase of clinical development for human use, as a drug candidate for the treatment of MDC1A.

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“…In addition to Lama1 upregulation described in this study, a number of disease modifying strategies are currently being explored in MDC1A animal models, such as treatment with miniaturized agrin [20][21][22] and laminin-α1 LN-domain nidogen-1 (αLNNd) [23][24][25] . 27 .…”

Section: E)mentioning

confidence: 99%

A mutation-independent approach via transcriptional upregulation of a disease modifier gene rescues muscular dystrophy in vivo

Kemaladewi

Lindsay

et al. 2018

Preprint

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Introductory paragraphIdentification of protective and/or pathogenic genetic modifiers provides important insight into the heterogeneity of disease presentations in individuals affected by neuromuscular disorders (NMDs), despite having well-defined pathogenic variants. Targeting modifier genes to improve disease phenotypes could be especially beneficial in cases where the causative genes are large, structurally complex and the mutations are heterogeneous. Here, we report a mutation-independent strategy to upregulate expression of a compensatory disease-modifying gene in Congenital Muscular Dystrophy type 1A (MDC1A) using a CRISPR/dCas9-based transcriptional activation system. MDC1A is caused by nonfunctional Laminin α2, which compromises muscle fibers stability and axon myelination in peripheral nerves 1. Transgenic overexpression of Lama1, encoding a structurally similar protein Laminin α1, ameliorates muscle wasting and paralysis in the MDC1A mouse models, demonstrating its role as a protective disease modifier 2. Yet, upregulation of Lama1 as a postnatal gene therapy is hampered by its large size, which exceeds the current genome packaging capacity of clinically relevant delivery vehicles such as adeno-associated viral vectors (AAVs). In this study, we sought to upregulate Lama1 using CRISPR/dCas9-based transcriptional activation system, comprised of catalytically inactive S. aureus Cas9 (dCas9) fused to VP64 transactivation domains and sgRNAs targeting the Lama1 promoter. We first demonstrated robust upregulation of Lama1 in myoblasts, and following AAV9-mediated intramuscular delivery, in skeletal muscles of dy2j/dy2j mouse model of MDC1A.We therefore assessed whether systemic upregulation of Lama1 would yield therapeutic benefits in dy2j/dy2j mice. When the intervention was started early in pre-symptomatic dy2j/dy2j mice, Lama1 upregulation prevented muscle fibrosis and hindlimb paralysis. An important question for future therapeutic approaches for a variety of disorders concerns the therapeutic window and phenotypic reversibility. This is particularly true for muscular dystrophies as it has long been hypothesized that fibrotic changes in skeletal muscle represent an irreversible disease state that would impair any therapeutic intervention at advanced stages of the disease. Here, we demonstrate that dystrophic features and disease progression were significantly improved and partially reversed when the treatment was initiated in symptomatic 3-week old dy2j/dy2j mice with already-apparent hind limb paralysis and significant muscle fibrosis.Collectively, our data demonstrate the feasibility and therapeutic benefit of CRISPR/dCas9-mediated modulation of a disease modifier gene, which opens up an entirely new and mutation-independent treatment approach for all MDC1A patients. Moreover, this treatment strategy provides evidence that muscle fibrosis can be reversible, thus extending the therapeutic window for this disorder. Our data provide a proof-of-concept strategy that can be applied to a variety of disease modifier genes and a powerful therapeutic approach for various inherited and acquired diseases.

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Overexpression of mini‐agrin in skeletal muscle increases muscle integrity and regenerative capacity in laminin‐α2‐deficient mice

Cited by 96 publications

References 32 publications

Lack of galectin‐1 results in defects in myoblast fusion and muscle regeneration

Lack of galectin‐1 results in defects in myoblast fusion and muscle regeneration

Omigapil Ameliorates the Pathology of Muscle Dystrophy Caused by Laminin-α2 Deficiency

A mutation-independent approach via transcriptional upregulation of a disease modifier gene rescues muscular dystrophy in vivo

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