Early skeletal muscle pathology and disease progress in the dy3K/dy3K mouse model of congenital muscular dystrophy with laminin α2 chain-deficiency

Gawlik, Kinga I.; Körner, Zandra; Oliveira, Bruno Menezes de; Durbeej, Madeleine

doi:10.1038/s41598-019-50550-0

Cited by 11 publications

(19 citation statements)

References 67 publications

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“…Muscle damage progresses quickly and already 4-day-old muscles show inflammatory response to injury. At day 7 the body weight is significantly reduced coinciding with pronounced loss of muscle fibers and inflammation (Figure 2; Miyagoe et al, 1997;Gawlik et al, 2019). The extracellular matrix components are massively upregulated, which is associated with muscle repair.…”

Section: Phenotype Of Dy 3k /Dy 3k Micementioning

confidence: 99%

“…Importantly, the severe phenotype observed at day 7 is partially ameliorated with age: at day 14 and 21 dy 3K /dy 3K muscles show recovery of muscle fiber number, reduced inflammation (Figure 2) and downregulation of fibronectin and collagen III ). Yet, apoptotic fibers and regenerating fibers are present at these stages (Miyagoe et al, 1997;Gawlik et al, 2019). Despite normalization of the number of myofibers, there is a decrease in fiber size and muscle mass (Carmignac et al, 2011a;Gawlik et al, 2019).…”

Section: Phenotype Of Dy 3k /Dy 3k Micementioning

confidence: 99%

“…Yet, apoptotic fibers and regenerating fibers are present at these stages (Miyagoe et al, 1997;Gawlik et al, 2019). Despite normalization of the number of myofibers, there is a decrease in fiber size and muscle mass (Carmignac et al, 2011a;Gawlik et al, 2019). Likewise, although the abundance of interstitial extracellular matrix is diminished in older mutants, the levels of collagen III and fibronectin remain elevated compared to a healthy agematched muscle ( Table 3).…”

Section: Phenotype Of Dy 3k /Dy 3k Micementioning

confidence: 99%

“…Non-limb muscles have been studied in the dy 3K /dy 3K mouse (Nystrom et al, 2006;Hager and Durbeej, 2009;Gawlik et al, 2014Gawlik et al, , 2019. The principal extraocular muscle and intrinsic laryngeal muscles appear spared (Nystrom et al, 2006;Hager and Durbeej, 2009), whereas accessory extraocular muscles show signs of myopathy .…”

Section: Phenotype Of Dy 3k /Dy 3k Micementioning

confidence: 99%

“…Mouse models for LAMA2-CMD have provided an excellent platform for studies of signaling events. Signaling cascades associated with apoptosis, inflammation, metabolism, regeneration, protein turnover, and fibrosis (GAPDH-Siah1-CBP/p300-p53, Akt, TGFβ, NFκB, p53, JAK/STAT, to mention a few) have been shown to be affected in laminin α2 chain-deficient murine muscle (Girgenrath et al, 2004(Girgenrath et al, , 2009Erb et al, 2009;Carmignac et al, 2011a,b;Kumar et al, 2011;Meinen et al, 2012;Elbaz et al, 2015;de Oliveira et al, 2014;Mehuron et al, 2014;Accorsi et al, 2015;Fontes-Oliveira et al, 2017;Gawlik et al, 2017Gawlik et al, , 2019Nunes et al, 2017;Pasteuning-Vuhman et al, 2018;Yoon et al, 2018). Additionally, microarray, RNA-sequencing and proteomic technologies were applied to study murine LAMA2-CMD dystrophic muscle and provided a global overview of the gene and protein expression changed upon laminin α2 chaindeficiency (van Lunteren et al, 2006;Hager et al, 2008;de Oliveira et al, 2014;Kemaladewi et al, 2017;Moreira Soares Oliveira et al, 2018;Yanay et al, 2019).…”

Section: Cellular and Molecular Events In Murine Laminin α2 Chain-defmentioning

confidence: 99%

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A Family of Laminin α2 Chain-Deficient Mouse Mutants: Advancing the Research on LAMA2-CMD

Gawlik

Durbeej

2020

Front. Mol. Neurosci.

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The research on laminin α2 chain-deficient congenital muscular dystrophy (LAMA2-CMD) advanced rapidly in the last few decades, largely due to availability of good mouse models for the disease and a strong interest in preclinical studies from scientists all over the world. These mouse models continue to provide a solid platform for understanding the LAMA2-CMD pathology. In addition, they enable researchers to test laborious, necessary routines, but also the most creative scientific approaches in order to design therapy for this devastating disorder. In this review we present animals belonging to the laminin α2 chain-deficient "dy/dy" mouse family (dy/dy, dy 2J /dy 2J , dy 3K /dy 3K , dy W /dy W , et al.) and a summary of the scientific progress they facilitated. We also raise a few questions that need to be addressed in order to maximize the usefulness of laminin α2 murine mutants and to further advance the LAMA2-CMD studies. We believe that research opportunities offered by the mouse models for LAMA2-CMD will continuously support our efforts to find a treatment for the disease.

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Section: Phenotype Of Dy 3k /Dy 3k Micementioning

confidence: 99%

Section: Phenotype Of Dy 3k /Dy 3k Micementioning

confidence: 99%

Section: Phenotype Of Dy 3k /Dy 3k Micementioning

confidence: 99%

Section: Phenotype Of Dy 3k /Dy 3k Micementioning

confidence: 99%

Section: Cellular and Molecular Events In Murine Laminin α2 Chain-defmentioning

confidence: 99%

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A Family of Laminin α2 Chain-Deficient Mouse Mutants: Advancing the Research on LAMA2-CMD

Gawlik

Durbeej

2020

Front. Mol. Neurosci.

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Weighted gene co-expression network analysis identifies molecular pathways and hub genes involved in broiler White Striping and Wooden Breast myopathies

Bordini

Zappaterra

Soglia

et al. 2021

Sci Rep

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In recent years, the poultry industry has experienced an increased incidence of myopathies affecting breasts of fast-growing broilers, such as White Striping (WS) and Wooden Breast (WB) defects. To explore the molecular mechanisms and genes involved in WS and WB onset, we decided to perform a Weighted Gene Co-expression Network Analysis (WGCNA) using the gene expression profile and meat quality parameters of Pectoralis major muscles analysed in our previous study. Among the 212 modules identified by WGCNA, the red, darkred, midnightblue and paleturquoise4 modules were chosen for subsequent analysis. Functional analysis evidenced pathways involved in extracellular matrix (ECM) organization, collagen metabolism, cellular signaling and unfolded protein response. The hub gene analysis showed several genes coding for ECM components as the most interconnected nodes in the gene network (e.g. COL4A1, COL4A2, LAMA2, LAMA4, FBLN5 and FBN1). In this regard, this study suggests that alterations in ECM composition could somehow activate the cascade of biological reactions that result in the growth-related myopathies onset, and the involvement of Collagen IV alterations in activating the endoplasmic reticulum (ER) stress response may be hypothesized. Therefore, our findings provide further and innovative knowledge concerning the molecular mechanisms related to the breast abnormalities occurrence in modern broilers.

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Thrombospondin-4 deletion does not exacerbate muscular dystrophy in β-sarcoglycan-deficient and laminin α2 chain-deficient mice

Zarén,

Gawlik

2024

Sci Rep

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Muscular dystrophy is a group of genetic disorders that lead to muscle wasting and loss of muscle function. Identifying genetic modifiers that alleviate symptoms or enhance the severity of a primary disease helps to understand mechanisms behind disease pathology and facilitates discovery of molecular targets for therapy. Several muscular dystrophies are caused by genetic defects in the components of the dystrophin-glycoprotein adhesion complex (DGC). Thrombospondin-4 overexpression has been shown to mitigate dystrophic disease in mouse models for Duchenne muscular dystrophy (dystrophin deficiency) and limb-girdle muscular dystrophy type 2F (LGMD2F, δ-sarcoglycan deficiency), while deletion of the thrombospondin-4 gene exacerbated the diseases. Hence, thrombospondin-4 has been considered a candidate molecule for therapy of muscular dystrophies involving the DGC. We have investigated whether thrombospondin-4 could act as a genetic modifier for other DGC-associated diseases: limb-girdle muscular dystrophy type 2E (LGMD2E, β-sarcoglycan deficiency) and laminin α2 chain-deficient muscular dystrophy (LAMA2-RD). Deletion of the thrombospondin-4 gene in mouse models for LGMD2E and LAMA2-RD, respectively, did not result in worsening of the dystrophic phenotype. Loss of thrombospondin-4 did not enhance sarcolemma damage and did not impair trafficking of transmembrane receptors integrin α7β1 and dystroglycan in double knockout muscles. Our results suggest that thrombospondin-4 might not be a relevant therapeutic target for all muscular dystrophies involving the DGC. This data also demonstrates that molecular pathology between very similar diseases like LGMD2E and 2F can differ significantly.

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Early skeletal muscle pathology and disease progress in the dy3K/dy3K mouse model of congenital muscular dystrophy with laminin α2 chain-deficiency

Cited by 11 publications

References 67 publications

A Family of Laminin α2 Chain-Deficient Mouse Mutants: Advancing the Research on LAMA2-CMD

A Family of Laminin α2 Chain-Deficient Mouse Mutants: Advancing the Research on LAMA2-CMD

Weighted gene co-expression network analysis identifies molecular pathways and hub genes involved in broiler White Striping and Wooden Breast myopathies

Thrombospondin-4 deletion does not exacerbate muscular dystrophy in β-sarcoglycan-deficient and laminin α2 chain-deficient mice

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