mdx Mice Manifest More Severe Muscle Dysfunction and Diaphragm Force Deficits than Do mdx Mice

Beastrom, Nicholas; Lu, Haiyan; Macke, Allison; Canan, Benjamin D.; Johnson, Eric K.; Penton, Christopher; Kaspar, Brian K.; Rodino‐Klapac, Louise R.; Zhou, Lan; Janssen, Paul M. L.; Montanaro, Federica

doi:10.1016/j.ajpath.2011.07.009

Cited by 48 publications

(63 citation statements)

References 68 publications

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“…We next performed physiological assays on isolated groups of muscles (EDL, soleus, and diaphragm strips) biopsied from adult WT, Tg(CmkMir486), Dmd mdx-5Cv , and Dmd mdx-5Cv Tg(Cmk-Mir486) age-matched cohorts. The specific force (tetanic force per muscle physiological CSA) of EDL, soleus, and diaphragm muscles is reduced in Dmd mdx and Dmd mdx-5Cv mice (29,47). We observed no significant differences in specific force in the muscles of WT versus Tg(CmkMir486) mice, but a marked improvement in the muscles from Dmd mdx-5Cv Tg(Cmk-Mir486) mice when directly compared with Dmd mdx-5Cv littermates ( Figure 4C).…”

Section: Figurementioning

confidence: 69%

“…It has been well documented that dystrophic disease symptoms, such as muscle weakness, increased serum CK levels, and loss of muscle force, occur in aged Dmd mdx mice (54). In the more severe dystrophic Dmd mdx-5Cv mice, muscle fatigue and functional deficits have been reported as early as 8 weeks and progressively worsen in mice that have been aged to 1 year (29). To determine whether the beneficial effects observed in the adult 2-to 4-month-old mice were maintained in aged dystrophic muscles, we performed similar histological, biochemical, and physiological measurements on aged Dmd mdx-5Cv (10 to 14 months old) mice that overexpressed the miR-486 transgene.…”

Section: Figurementioning

confidence: 99%

“…Histological examination of the gastrocnemius muscles from adult Dmd mdx-5Cv Tg(Cmk-Mir486) mice also displayed improved overall histology and reduced numbers of centralized myonuclei, further supporting a functional role for miR-486 overexpression as a means of delaying the disease progression of muscular dystrophy (Supplemental Figure 2, A and B). A previous study has shown that the diaphragm muscle of the Dmd mdx-5Cv strain is more severely affected by dystrophin deficiency than other muscles (29). We measured the muscle fiber cross-sectional area (CSA) in WT, Tg(Cmk-Mir486), Dmd mdx-5Cv , and Dmd mdx-5Cv Tg(Cmk-Mir486) mice to determine what effects miR-486 might have on overall myofiber size.…”

Section: Mir-486 Is Enriched In Myogenic Tissues But Reduced In Dystrmentioning

confidence: 99%

“…An ENU-mutagenesis screen later identified several additional mouse strains containing mutations elsewhere in the mouse Dmd gene (27). One strain of dystrophic mice from that screen, Dmd mdx-5Cv , contains a nonsense mutation in exon 10, shows the fewest number of revertant fibers among all the Dmd mdx mouse strains, and has a severe diaphragm muscle-force deficit (28,29). Given the severity of the disease phenotypes observed in the Dmd mdx-5Cv mice, this mouse strain is highly useful for testing novel drug compounds and factors that might ameliorate clinical pathological aspects of dystrophin deficiency in an animal model.…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

Alexander¹,

Casar²,

Matsuki³

et al. 2014

J. Clin. Invest.

120

122

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Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, which resultsin dysfunctional signaling pathways within muscle. Previously, we identified microRNA-486 (miR-486) as a muscle-enriched microRNA that is markedly reduced in the muscles of dystrophin-deficient mice (Dmd mdx-5Cv mice) and in DMD patient muscles. Here, we determined that muscle-specific transgenic overexpression of miR-486 in muscle of Dmd mdx-5Cv mice results in reduced serum creatine kinase levels, improved sarcolemmal integrity, fewer centralized myonuclei, increased myofiber size, and improved muscle physiology and performance. Additionally, we identified dedicator of cytokinesis 3 (DOCK3) as a miR-486 target in skeletal muscle and determined that DOCK3 expression is induced in dystrophic muscles. DOCK3 overexpression in human myotubes modulated PTEN/AKT signaling, which regulates muscle hypertrophy and growth, and induced apoptosis. Furthermore, several components of the PTEN/AKT pathway were markedly modulated by miR-486 in dystrophin-deficient muscle. Skeletal muscle-specific miR-486 overexpression in Dmd mdx-5Cv animals decreased levels of DOCK3, reduced PTEN expression, and subsequently increased levels of phosphorylated AKT, which resulted in an overall beneficial effect. Together, these studies demonstrate that stable overexpression of miR-486 ameliorates the disease progression of dystrophin-deficient skeletal muscle.

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Section: Figurementioning

confidence: 69%

Section: Figurementioning

confidence: 99%

Section: Mir-486 Is Enriched In Myogenic Tissues But Reduced In Dystrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

Alexander¹,

Casar²,

Matsuki³

et al. 2014

J. Clin. Invest.

120

122

View full text Add to dashboard Cite

show abstract

“…Mdx 5cv mice, instead of mdx mice, were used because the mdx 5cv mice are in the C57BL/6J background, same as the ColI-GFP and Ccr2−/− mice. Mdx 5cv mice showed muscle pathology comparable to mdx mice (41). Mdx 5cv mice were derived from the Jackson laboratory.…”

Section: Methodsmentioning

confidence: 95%

Identification and Function of Fibrocytes in Skeletal Muscle Injury Repair and Muscular Dystrophy

Wang

Zhao

Ransohoff

et al. 2016

The Journal of Immunology

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We identified and characterized the function of CD45+/Collagen I+ fibrocytes in acutely injured skeletal muscle of wild-type and Ccr2−/− mice, and in quadriceps and diaphragm muscles of mdx5cv mice, a mouse model for Duchenne muscular dystrophy. Fibrocytes were not detected in peripheral blood of wild-type mice after acute muscle injury or mdx5cv mice. Fibrocytes were detected in acutely injured muscles and in mdx5cv quadriceps and diaphragm muscles. These cells expressed F4/80 and CCR2, and they were mostly Ly6Clow. They expressed a low level of collagens but a high level of pro-fibrotic growth factors as compared with intramuscular fibroblasts. Fibrocyte expression of collagens and pro-fibrotic growth factors was not increased in Ccr2−/− mice as compared with wild-type controls. Fibrocyte expression of both pro-inflammatory and pro-fibrotic cytokines was significantly higher in mdx5cv diaphragm than in mdx5cv quadriceps. In co-cultures, fibrocytes from the mdx5cv diaphragm stimulated a higher level of fibroblast expression of extracellular matrix genes than those from the mdx5cv quadriceps. Our findings suggest that intramuscular fibrocytes most likely originate from infiltrating monocytes/macrophages and differentiate within injured muscles. They likely contribute to the normal muscle injury repair by producing growth factors. They do not appear to contribute to the persistent muscle fibrosis associated with poor injury repair in Ccr2−/− mice. But they likely contribute to the persistent inflammation and progressive fibrosis in mdx5cv diaphragm.

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AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models

Sondergaard

Griffin

Pozsgai

et al. 2015

Ann Clin Transl Neurol

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ObjectiveDysferlinopathies are a family of untreatable muscle disorders caused by mutations in the dysferlin gene. Lack of dysferlin protein results in progressive dystrophy with chronic muscle fiber loss, inflammation, fat replacement, and fibrosis; leading to deteriorating muscle weakness. The objective of this work is to demonstrate efficient and safe restoration of dysferlin expression following gene therapy treatment.MethodsTraditional gene therapy is restricted by the packaging capacity limit of adeno-associated virus (AAV), however, use of a dual vector strategy allows for delivery of over-sized genes, including dysferlin. The two vector system (AAV.DYSF.DV) packages the dysferlin cDNA utilizing AAV serotype rh.74 through the use of two discrete vectors defined by a 1 kb region of homology. Delivery of AAV.DYSF.DV via intramuscular and vascular delivery routes in dysferlin deficient mice and nonhuman primates was compared for efficiency and safety.ResultsTreated muscles were tested for dysferlin expression, overall muscle histology, and ability to repair following injury. High levels of dysferlin overexpression was shown for all muscle groups treated as well as restoration of functional outcome measures (membrane repair ability and diaphragm specific force) to wild-type levels. In primates, strong dysferlin expression was demonstrated with no safety concerns.InterpretationTreated muscles showed high levels of dysferlin expression with functional restoration with no evidence of toxicity or immune response providing proof of principle for translation to dysferlinopathy patients.

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mdx Mice Manifest More Severe Muscle Dysfunction and Diaphragm Force Deficits than Do mdx Mice

Cited by 48 publications

References 68 publications

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

Identification and Function of Fibrocytes in Skeletal Muscle Injury Repair and Muscular Dystrophy

AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models

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