scholarly journals Current understanding and treatment of cardiac and skeletal muscle pathology in laminin-α2 chain-deficient congenital muscular dystrophy

2019 ◽  
Vol Volume 12 ◽  
pp. 113-130 ◽  
Author(s):  
Quynh Nguyen ◽  
Kenji Rowel Q Lim ◽  
Toshifumi Yokota
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Congenital Muscular Dystrophy ◽  
Current Understanding ◽  
Muscle Pathology ◽  
Laminin Α2

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

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kinga I. Gawlik ◽  
Zandra Körner ◽  
Bruno M. Oliveira ◽  
Madeleine Durbeej
Keyword(s):  
Muscular Dystrophy ◽  
Mouse Model ◽  
Congenital Muscular Dystrophy ◽  
Masticatory Muscles ◽  
Severe Form ◽  
Matrix Proteins ◽  
Muscle Pathology ◽  
Muscle Fibres ◽  
Disease Initiation ◽  
Laminin Α2

Abstract Deficiency of laminin α2 chain leads to a severe form of congenital muscular dystrophy (LAMA2-CMD), and dystrophic symptoms progress rapidly in early childhood. Currently, there is no treatment for this detrimental disorder. Development of therapies is largely hindered by lack of understanding of mechanisms involved in the disease initiation and progress, both in patients but also in mouse models that are commonly used in the preclinical setup. Here, we unveil the first pathogenic events and characterise the disease development in a mouse model for LAMA2-CMD (dy3K/dy3K), by analysing muscles at perinatal, neonatal and postnatal stages. We found that apoptotic muscle fibres were present as early as postnatal day 1. Other typical dystrophic hallmarks (muscle degeneration, inflammation, and extensive production of the extracellular matrix proteins) were clearly evident already at postnatal day 4, and the highest degree of muscle deterioration was reached by day 7. Interestingly, the severe phenotype of limb muscles partially recovered on days 14 and 21, despite worsening of the general condition of the dy3K/dy3K mouse by that age. We found that masticatory muscles were severely affected in dy3K/dy3K mice and this may be an underlying cause of their malnutrition, which contributes to death around day 21. We also showed that several signalling pathways were affected already in 1-day-old dy3K/dy3K muscle. Therapeutic tests in the dy3K/dy3K mouse model should therefore be initiated shortly after birth, but should also take into account timing and correlation between regenerative and pathogenic events.

scholarly journals Laminin-111 protein therapy after disease onset slows muscle disease in a mouse model of laminin-α2 related congenital muscular dystrophy

2020 ◽  
Vol 29 (13) ◽  
pp. 2162-2170
Author(s):  
Pamela Barraza-Flores ◽  
Katherine E Bukovec ◽  
Marisela Dagda ◽  
Brandon W Conner ◽  
Ariany Oliveira-Santos ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Life Expectancy ◽  
Mouse Model ◽  
Replacement Therapy ◽  
Disease Onset ◽  
Congenital Muscular Dystrophy ◽  
Muscle Disease ◽  
Muscle Pathology ◽  
Protein Therapy ◽  
Laminin Α2

Abstract Laminin-α2 related congenital muscular dystrophy (LAMA2-CMD) is a fatal muscle disease caused by mutations in the LAMA2 gene. Laminin-α2 is critical for the formation of laminin-211 and -221 heterotrimers in the muscle basal lamina. LAMA2-CMD patients exhibit hypotonia from birth and progressive muscle loss that results in developmental delay, confinement to a wheelchair, respiratory insufficiency and premature death. There is currently no cure or effective treatment for LAMA2-CMD. Several studies have shown laminin-111 can serve as an effective protein-replacement therapy for LAMA2-CMD. Studies have demonstrated early treatment with laminin-111 protein results in an increase in life expectancy and improvements in muscle pathology and function. Since LAMA2-CMD patients are often diagnosed after advanced disease, it is unclear if laminin-111 protein therapy at an advanced stage of the disease can have beneficial outcomes. In this study, we tested the efficacy of laminin-111 protein therapy after disease onset in a mouse model of LAMA2-CMD. Our results showed laminin-111 treatment after muscle disease onset increased life expectancy, promoted muscle growth and increased muscle stiffness. Together these studies indicate laminin-111 protein therapy either early or late in the disease process could serve as an effective protein replacement therapy for LAMA2-CMD.

Secondary reduction of α7B integrin in laminin α2 deficient congenital muscular dystrophy supports an additional transmembrane link in skeletal muscle

1999 ◽  
Vol 163 (2) ◽  
pp. 140-152 ◽  
Author(s):  
Ronald D. Cohn ◽  
Ulrike Mayer ◽  
Gesine Saher ◽  
Ralf Herrmann ◽  
Arjan van der Flier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Congenital Muscular Dystrophy ◽  
Laminin Α2

scholarly journals Antioxidants Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy

Antioxidants ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 244 ◽  
Author(s):  
Vahid M. Harandi ◽  
Bernardo Moreira Soares Oliveira ◽  
Valérie Allamand ◽  
Ariana Friberg ◽  
Cibely C. Fontes-Oliveira ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Vitamin E ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Congenital Muscular Dystrophy ◽  
Neuromuscular Disorder ◽  
Oxygen Homeostasis ◽  
And Oxidative Stress ◽  
Laminin Α2

Congenital muscular dystrophy with laminin α2 chain-deficiency (LAMA2-CMD) is a severe neuromuscular disorder without a cure. Using transcriptome and proteome profiling as well as functional assays, we previously demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models. Reactive oxygen species (ROS) increase when oxygen homeostasis is not maintained and, here, we investigate whether oxidative stress indeed is involved in the pathogenesis of LAMA2-CMD. We also analyze the effects of two antioxidant molecules, N-acetyl-L-cysteine (NAC) and vitamin E, on disease progression in the dy2J/dy2J mouse model of LAMA2-CMD. We demonstrate increased ROS levels in LAMA2-CMD mouse and patient skeletal muscle. Furthermore, NAC treatment (150 mg/kg IP for 6 days/week for 3 weeks) led to muscle force loss prevention, reduced central nucleation and decreased the occurrence of apoptosis, inflammation, fibrosis and oxidative stress in LAMA2-CMD muscle. In addition, vitamin E (40 mg/kg oral gavage for 6 days/week for 2 weeks) improved morphological features and reduced inflammation and ROS levels in dy2J/dy2J skeletal muscle. We suggest that NAC and to some extent vitamin E might be potential future supportive treatments for LAMA2-CMD as they improve numerous pathological hallmarks of LAMA2-CMD.

scholarly journals Improving Reproducibility of Phenotypic Assessments in the DyW Mouse Model of Laminin-α2 Related Congenital Muscular Dystrophy

2017 ◽  
Vol 4 (2) ◽  
pp. 115-126 ◽  
Author(s):  
Raffaella Willmann ◽  
Heather Gordish-Dressman ◽  
Sarina Meinen ◽  
Markus A. Rüegg ◽  
Qing Yu ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Mouse Model ◽  
Congenital Muscular Dystrophy ◽  
Laminin Α2
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