Muscle Structure Influences Utrophin Expression in mdx Mice
| Autor: | Guy L. Odom, Ariana C. Combs, Robert J. Bloch, Glen B. Banks, Jeffrey S. Chamberlain |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Cancer Research Heredity Utrophin Genetic Linkage Duchenne muscular dystrophy Muscle Proteins Duchenne Muscular Dystrophy Sarcomere Desmin Dystrophin Mice 0302 clinical medicine Sarcolemma Medicine and Health Sciences Muscular dystrophy Genetics (clinical) Mice Knockout 0303 health sciences biology Anatomy musculoskeletal system medicine.anatomical_structure Sex Linkage X-Linked Traits Research Article Sarcomeres medicine.medical_specialty lcsh:QH426-470 Thoracic diaphragm 03 medical and health sciences Internal medicine medicine Genetics Animals Muscle Skeletal Molecular Biology Ecology Evolution Behavior and Systematics 030304 developmental biology Clinical Genetics Elapid Venoms Inflammation Macrophages Calcium-Binding Proteins Biology and Life Sciences Membrane Proteins Human Genetics medicine.disease Muscular Dystrophy Duchenne lcsh:Genetics Endocrinology Dystrophin-Associated Proteins biology.protein Mice Inbred mdx 030217 neurology & neurosurgery |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 10, Iss 6, p e1004431 (2014) |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder caused by mutations in the dystrophin gene. To examine the influence of muscle structure on the pathogenesis of DMD we generated mdx4cv:desmin double knockout (dko) mice. The dko male mice died of apparent cardiorespiratory failure at a median age of 76 days compared to 609 days for the desmin−/− mice. An ∼2.5 fold increase in utrophin expression in the dko skeletal muscles prevented necrosis in ∼91% of 1a, 2a and 2d/x fiber-types. In contrast, utrophin expression was reduced in the extrasynaptic sarcolemma of the dko fast 2b fibers leading to increased membrane fragility and dystrophic pathology. Despite lacking extrasynaptic utrophin, the dko fast 2b fibers were less dystrophic than the mdx4cv fast 2b fibers suggesting utrophin-independent mechanisms were also contributing to the reduced dystrophic pathology. We found no overt change in the regenerative capacity of muscle stem cells when comparing the wild-type, desmin−/−, mdx4cv and dko gastrocnemius muscles injured with notexin. Utrophin could form costameric striations with α-sarcomeric actin in the dko to maintain the integrity of the membrane, but the lack of restoration of the NODS (nNOS, α-dystrobrevin 1 and 2, α1-syntrophin) complex and desmin coincided with profound changes to the sarcomere alignment in the diaphragm, deposition of collagen between the myofibers, and impaired diaphragm function. We conclude that the dko mice may provide new insights into the structural mechanisms that influence endogenous utrophin expression that are pertinent for developing a therapy for DMD. Author Summary Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder caused by mutations in the dystrophin gene. Utrophin is structurally similar to dystrophin and improving its expression can prevent skeletal muscle necrosis in the mdx mouse model of DMD. Consequently, improving utrophin expression is a primary therapeutic target for treating DMD. While the downstream mechanisms that influence utrophin expression and stability are well described, the upstream mechanisms are less clear. Here, we found that perturbing the highly ordered structure of striated muscle by genetically deleting desmin from mdx mice increased utrophin expression to levels that prevented skeletal muscle necrosis. Thus, the mdx:desmin double knockout mice may prove valuable in determining the upstream mechanisms that influence utrophin expression to develop a therapy for DMD. |
| Databáze: | OpenAIRE |
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