Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy

Grounds, Miranda D.; Radley‐Crabb, Hannah G.; Lynch, Gordon S.; Nagaraju, Kanneboyina; A, De Luca

doi:10.1016/j.nbd.2008.03.008

Cited by 299 publications

(446 citation statements)

References 194 publications

(316 reference statements)

Supporting

Mentioning

386

Contrasting

Unclassified

Order By: Relevance

“…In mdx mice there was progressive muscle degeneration starting by 3 wks of age. Muscle atrophy, inflammation and fibrosis are detected in the mdx mice at 8 wks of age in coincidence with a decrease in strength of the forelimb (16). Thus, this analysis in mdx mice between 1.5 and 3.5 months should capture the effect of the treatment with HDACi on the morphohistological and functional parameters of disease progression.…”

Section: + ⋅Aucmentioning

confidence: 96%

Preclinical Studies in the mdx Mouse Model of Duchenne Muscular Dystrophy with the Histone Deacetylase Inhibitor Givinostat

Consalvi

Mozzetta

Bettica

et al. 2013

Mol Med

119

View full text Add to dashboard Cite

Previous work has established the existence of dystrophin-nitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions that target HDACs (that is, HDAC inhibitors) are of potential therapeutic interest for the treatment of muscular dystrophies. In this study, we explored the effectiveness of long-term treatment with different doses of the HDAC inhibitor givinostat in mdx mice-the mouse model of Duchenne muscular dystrophy (DMD). This study identified an efficacy for recovering functional and histological parameters within a window between 5 and 10 mg/kg/d of givinostat, with evident reduction of the beneficial effects with 1 mg/kg/d dosage. The long-term (3.5 months) exposure of 1.5-month-old mdx mice to optimal concentrations of givinostat promoted the formation of muscles with increased cross-sectional area and reduced fibrotic scars and fatty infiltration, leading to an overall improvement of endurance performance in treadmill tests and increased membrane stability. Interestingly, a reduced inflammatory infiltrate was observed in muscles of mdx mice exposed to 5 and 10 mg/kg/d of givinostat. A parallel pharmacokinetic/pharmacodynamic analysis confirmed the relationship between the effective doses of givinostat and the drug distribution in muscles and blood of treated mice. These findings provide the preclinical basis for an immediate translation of givinostat into clinical studies with DMD patients.

show abstract

Section: + ⋅Aucmentioning

confidence: 96%

Preclinical Studies in the mdx Mouse Model of Duchenne Muscular Dystrophy with the Histone Deacetylase Inhibitor Givinostat

Consalvi

Mozzetta

Bettica

et al. 2013

Mol Med

119

View full text Add to dashboard Cite

show abstract

“…The mdx mouse strain, lacking a functional dystrophin gene, has served as the animal model for human DMD and Becker muscular dystrophies [10]. However, while the skeletal muscles of mdx mice undergo extensive necrosis early in neonatal life, unlike the human disease, the affected muscle rapidly regenerates and regains structural and functional integrity [8,[11][12][13]. The enhanced regenerative potential of mdx muscles and the upregulation of compensatory proteins, such as utrophin and integrins, are thought to be the basis of the reduced wasting of dystrophin-deficient muscles in mdx [14].…”

Section: Animal Models Of Muscular Dystrophymentioning

confidence: 99%

“…Although the genetic basis of DMD pathology has been known for more than 30 years and a mouse model (mdx) has been developed, mechanisms leading to the extensive muscle wasting observed in DMD patients remain to be fully elucidated [8]. Indeed, while dystrophin deficiency is the primary genetic defect, secondary mechanisms are important features of the disease.…”

Section: Introductionmentioning

confidence: 99%

Insights into the Pathogenic Secondary Symptoms Caused by the Primary Loss of Dystrophin

Forcina

Pelosi

Miano

et al. 2017

JFMK

View full text Add to dashboard Cite

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease in which the dystrophin gene is mutated, resulting in dysfunctional dystrophin protein. Without dystrophin, the dystrophin-glycoprotein complex (DGC) is unstable, leading to an increase in muscle damage. Moreover, the imbalance between muscle damage and repair leads to a chronic inflammatory response and an increase in the amount of fibrosis over time. The absence of dystrophin at the sarcolemma also delocalizes and downregulates nitric oxide synthase (nNOS) and alters enzymatic antioxidant responses, leading to an increase in oxidative stress. In this review, we analyze the pathogenic role of both inflammation and oxidative stress in muscular dystrophy.

show abstract

“…1,2 DMD is characterized by progressive muscle weakness and wasting, and neural dysfunctions involving mental retardation and metabolic alterations have also been described. 3 The molecular mechanisms underlying dystrophic brain dysfunction in DMD have not been completely clarified.…”

mentioning

confidence: 99%

Effects of prednisolone on the dystrophin-associated proteins in the blood–brain barrier and skeletal muscle of dystrophic mdx mice

Tamma

Annese

Capogrosso

et al. 2013

Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

The mdx mouse, the most widely used animal model of Duchenne muscular dystrophy (DMD), develops a seriously impaired blood-brain barrier (BBB). As glucocorticoids are used clinically to delay the progression of DMD, we evaluated the effects of chronic treatment with a-methyl-prednisolone (PDN) on the expression of structural proteins and markers in the brain and skeletal muscle of the mdx mouse. We analyzed the immunocytochemical and biochemical expression of four BBB markers, including endothelial ZO-1 and occludin, desmin in pericytes, and glial fibrillary acidic protein (GFAP) in glial cells, and the expression of the short dystrophin isoform Dp 71, the dystrophin-associated proteins (DAPs), and aquaporin-4 (AQP4) and a-b dystroglycan (DG) in the brain. We evaluated the BBB integrity of mdx and PDN-treated mdx mice by means of intravascular injection of horseradish peroxidase (HRP). The expression of DAPs was also assessed in gastrocnemius muscles and correlated with utrophin expression, and laminin content was measured in the muscle and brain. PDN treatment induced a significant increase in the mRNA and protein content of the BBB markers; a reduction in the phosphorylation of occludin in the brain and of AQP4/b DG in both tissues; an increase of Dp71 protein content; and an increase of both mRNA and protein levels of the AQP4/a-b DG complex. The latter was associated with enhanced laminin and utrophin in the muscle. The HRP assay demonstrated functional restoration of the BBB in the PDN-treated mdx mice. Specifically, mdx mice showed extensive perivascular labeling due to escape of the marker, while HRP was exclusively intravascular in the PDN-treated mice and the controls. These data illustrate for the first time that PDN reverses the BBB alterations in the mdx mouse and re-establishes the proper expression and phosphorylation of b-DG in both the BBB and skeletal muscle. Further, PDN partially protects against muscle damage. The reduction in AQP4 and occludin phosphorylation, coupled with their anchoring to glial and endothelial membranes in PDN-treated mice, suggests that the drug may target the glial and endothelial cells. Our results suggest a novel mechanism for PDN action on cerebral and muscular function, restoring the link between DAPs and the extracellular matrix, most likely through protein kinase inactivation.

show abstract

Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy

Cited by 299 publications

References 194 publications

Preclinical Studies in the mdx Mouse Model of Duchenne Muscular Dystrophy with the Histone Deacetylase Inhibitor Givinostat

Preclinical Studies in the mdx Mouse Model of Duchenne Muscular Dystrophy with the Histone Deacetylase Inhibitor Givinostat

Insights into the Pathogenic Secondary Symptoms Caused by the Primary Loss of Dystrophin

Effects of prednisolone on the dystrophin-associated proteins in the blood–brain barrier and skeletal muscle of dystrophic mdx mice

Contact Info

Product

Resources

About