Animal Models of Muscular Dystrophy

Division of Medical Genetics, Department of Neurology, University of Washington, Seattle, Washington, USA.
Progress in molecular biology and translational science (Impact Factor: 3.49). 01/2012; 105:83-111. DOI: 10.1016/B978-0-12-394596-9.00004-4
Source: PubMed


The muscular dystrophies (MDs) represent a diverse collection of inherited human disorders, which affect to varying degrees skeletal, cardiac, and sometimes smooth muscle (Emery, 2002). To date, more than 50 different genes have been implicated as causing one or more types of MD (Bansal et al., 2003). In many cases, invaluable insights into disease mechanisms, structure and function of gene products, and approaches for therapeutic interventions have benefited from the study of animal models of the different MDs (Arnett et al., 2009). The large number of genes that are associated with MD and the tremendous number of animal models that have been developed preclude a complete discussion of each in the context of this review. However, we summarize here a number of the more commonly used models together with a mixture of different types of gene and MD, which serves to give a general overview of the value of animal models of MD for research and therapeutic development.

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    • "LGMD2B, Miyoshi myopathy, and distal myopathy are progressive dystrophies that present clinically as weakness in the proximal or distal muscles with elevated serum CK and muscle degeneration (Nigro, 2003; Klinge et al., 2008; Amato and Brown, 2011). These diseases are established as late-adult onset both clinically (Gordon et al., 1993; Klinge et al., 2008; Angelini et al., 2010, 2011; Gayathri et al., 2011) as well as in preclinical models (Turk et al., 2006; Nemoto et al., 2007; Ng et al., 2012). While these disorders have been linked to the mutation or ablation of the dysferlin gene (DYSF) (Illarioshkin et al., 2000; Vainzof et al., 2001; Nguyen et al., 2005; Cacciottolo et al., 2011), a consensus on the mechanistic basis of disease has not been reached. "
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    ABSTRACT: Oxidative stress is a critical disease modifier in the muscular dystrophies. Recently, we discovered a pathway by which mechanical stretch activates NADPH Oxidase 2 (Nox2) dependent ROS generation (X-ROS). Our work in dystrophic skeletal muscle revealed that X-ROS is excessive in dystrophin-deficient (mdx) skeletal muscle and contributes to muscle injury susceptibility, a hallmark of the dystrophic process. We also observed widespread alterations in the expression of genes associated with the X-ROS pathway and redox homeostasis in muscles from both Duchenne muscular dystrophy patients and mdx mice. As nuclear factor erythroid 2-related factor 2 (Nrf2) plays an essential role in the transcriptional regulation of genes involved in redox homeostasis, we hypothesized that Nrf2 deficiency may contribute to enhanced X-ROS signaling by reducing redox buffering. To directly test the effect of diminished Nrf2 activity, Nrf2 was genetically silenced in the A/J model of dysferlinopathy-a model with a mild histopathologic and functional phenotype. Nrf2-deficient A/J mice exhibited significant muscle-specific functional deficits, histopathologic abnormalities, and dramatically enhanced X-ROS compared to control A/J and WT mice, both with functional Nrf2. Having identified that reduced Nrf2 activity is a negative disease modifier, we propose that strategies targeting Nrf2 activation may address the generalized reduction in redox homeostasis to halt or slow dystrophic progression.
    Full-text · Article · Feb 2014 · Frontiers in Physiology
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    • "Amplex Red assay kit, dihydroxyethidium, BODIPY 581/591 undecanoic acid, and 4-amino-5-methylamino-2,7-difluorofluorescein-diace- tate (DAF-FM-DA) were obtained from Invitrogen. Human Tissue Samples—Patients (n 103; age 1.1– 65 years) with muscle diseases evaluated at the Neuromuscular Disorders Clinic, NIMHANS, Bangalore, India, during 2006 – 2012, were selected following diagnostic procedures. The muscle strength of patients (based on the Medical Research Council scale (11)) was recorded by the neurologist and graded 0 to 5 (supplemental " Experimental Procedures " ). "
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    ABSTRACT: Muscular dystrophies (MDs) and inflammatory myopathies (IMs) are debilitating skeletal muscle disorders characterized by common pathological events including myodegeneration and inflammation. However, an experimental model representing both muscle pathologies and displaying most of the distinctive markers has not been characterized. We investigated the cardiotoxin (CTX)-mediated transient acute mouse model of muscle degeneration and compared the cardinal features with human MDs and IMs. The CTX model displayed degeneration, apoptosis, inflammation, loss of sarcolemmal complexes, sarcolemmal disruption and ultrastructural changes characteristic of human MDs and IMs. Cell death caused by CTX involved calcium influx and mitochondrial damage both in murine C2C12 muscle cells and in mice. Mitochondrial proteomic analysis at the initial phase of degeneration in the model detected lowered expression of 80 mitochondrial proteins including subunits of respiratory complexes, ATP machinery, fatty acid metabolism and Krebs cycle, which further decreased in expression during the peak degenerative phase. The mass spectrometry (MS) data was supported by enzyme assays, western blot and histochemistry. CTX model also displayed markers of oxidative stress and lowered glutathione reduced/oxidized ratio (GSH/GSSG) similar to MDs, human myopathies and neurogenic atrophies. MS analysis identified 6 unique oxidized proteins from Duchenne muscular dystrophy (DMD) samples (n=6) (vs. controls; n=6), including two mitochondrial proteins. Interestingly, these mitochondrial proteins were down-regulated in the CTX model thereby linking oxidative stress and mitochondrial dysfunction. We conclude that mitochondrial alterations and oxidative damage significantly contribute to CTX-mediated muscle pathology with implications for human muscle diseases.
    Full-text · Article · Nov 2013 · Journal of Biological Chemistry
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