The mdx mouse model as a surrogate for<scp>D</scp>uchenne muscular dystrophy

Partridge, Terence A.

doi:10.1111/febs.12267

Cited by 162 publications

(159 citation statements)

References 72 publications

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“…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%

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

Forcina

Pelosi

Miano

et al. 2017

JFMK

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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.

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Section: Animal Models Of Muscular Dystrophymentioning

confidence: 99%

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

Forcina

Pelosi

Miano

et al. 2017

JFMK

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“…As a consequence, mdx mice have a near normal lifespan. Despite milder muscular histopathological defect compared to DMD, mdx mouse is considered a good model in which to study the muscle regeneration-degeneration mechanism [6,7]. In mdx mouse model, eccentric contractions enhanced force loss due to myofibrillar impairment [8].…”

Section: Introductionmentioning

confidence: 99%

Myofibrillar misalignment correlated to triad disappearance of mdx mouse gastrocnemius muscle probed by SHG microscopy

Rouède¹,

Coumailleau²,

Schaub³

et al. 2014

Biomed. Opt. Express

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Abstract:We show that the canonical single frequency sarcomeric SHG intensity pattern (SHG-IP) of control muscles is converted to double frequency sarcomeric SHG-IP in preserved mdx mouse gastrocnemius muscles in the vicinity of necrotic fibers. These double frequency sarcomeric SHG-IPs are often spatially correlated to double frequency sarcomeric two-photon excitation fluorescence (TPEF) emitted from Z-line and I-bands and to one centered spot SHG angular intensity pattern (SHG-AIP) suggesting that these patterns are signature of myofibrillar misalignement. This latter is confirmed with transmission electron microscopy (TEM). Moreover, a good spatial correlation between SHG signature of myofibrillar misalignment and triad reduction is established. Theoretical simulation of sarcomeric SHG-IP is used to demonstrate the correlation between change of SHG-IP and -AIP and myofibrillar misalignment. The extreme sensitivity of SHG microscopy to reveal the submicrometric organization of A-band thick filaments is highlighted. This report is a first step toward future studies aimed at establishing live SHG signature of myofibrillar misalignment involving excitation contraction defects due to muscle damage and disease. References and links1. K. P. Campbell and S. D. Kahl, "Association of dystrophin and an integral membrane glycoprotein," Nature 338(6212), 259-262 (1989). 2. E. E. Zubrzycka-Gaarn, D. E. Bulman, G. Karpati, A. H. Burghes, B. Belfall, H. J. Klamut, J. Talbot, R. S. Hodges, P. N. Ray, and R. G. Worton, "The Duchenne muscular dystrophy gene product is localized in sarcolemma of human skeletal muscle," Nature 333(6172), 466-469 (1988). 3. D. J. Blake, A. Weir, S. E. Newey, and K. E. Davies, "Function and genetics of dystrophin and dystrophinrelated proteins in muscle," Physiol. Rev. 82(2), 291-329 (2002). 4. J. G. Tidball and M. Wehling-Henricks, "The role of free radicals in the pathophysiology of muscular dystrophy," J. Appl. Physiol. 102(4), 1677-1686 (2006). 5. G. Bulfield, W. G. Siller, P. A. Wight, and K. J. Moore, "X chromosome-linked muscular dystrophy (mdx) in the mouse," Proc. Natl. Acad. Sci. U.S.A. 81(4), 1189-1192 (1984). 6. S. De la Porte, S. Morin, and J. Koenig, "Characteristics of skeletal muscle in mdx mutant mice," Int. Rev. Cytol. 191, 99-148 (1999). 7. T. A. Partridge, "The mdx mouse model as a surrogate for Duchenne muscular dystrophy," FEBS J. 280(17), 4177-4186 (2013 735-738 (1988). 12. M. J. Cullen, J. J. Fulthorpe, and J. B. Harris, "The distribution of desmin and titin in normal and dystrophic human muscle," Acta Neuropathol. 83(2), 158-169 (1992)

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“…Similar to DMD patients, the mdx mouse displays widespread muscle weakness, undergoes repetitive rounds of muscle degeneration and regeneration, and is highly susceptible to contraction-induced injury, losing almost all force-generating capacity after as few as five eccentric contractions (22)(23)(24)(25). However, although the mdx mouse recapitulates some phenotypes associated with DMD, it has a normal lifespan and presents with an overall milder phenotype than do DMD patients (26). This relatively mild dystrophic phenotype is partially attributed to up-regulation of the protein utrophin.…”

mentioning

confidence: 99%

Microtubule binding distinguishes dystrophin from utrophin

Belanto

Mader²,

Eckhoff³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

124

182

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Dystrophin and utrophin are highly similar proteins that both link cortical actin filaments with a complex of sarcolemmal glycoproteins, yet localize to different subcellular domains within normal muscle cells. In mdx mice and Duchenne muscular dystrophy patients, dystrophin is lacking and utrophin is consequently up-regulated and redistributed to locations normally occupied by dystrophin. Transgenic overexpression of utrophin has been shown to significantly improve aspects of the disease phenotype in the mdx mouse; therefore, utrophin up-regulation is under intense investigation as a potential therapy for Duchenne muscular dystrophy. Here we biochemically compared the previously documented microtubule binding activity of dystrophin with utrophin and analyzed several transgenic mouse models to identify phenotypes of the mdx mouse that remain despite transgenic utrophin overexpression. Our in vitro analyses revealed that dystrophin binds microtubules with high affinity and pauses microtubule polymerization, whereas utrophin has no activity in either assay. We also found that transgenic utrophin overexpression does not correct subsarcolemmal microtubule lattice disorganization, loss of torque production after in vivo eccentric contractions, or physical inactivity after mild exercise. Finally, our data suggest that exerciseinduced inactivity correlates with loss of sarcolemmal neuronal NOS localization in mdx muscle, whereas loss of in vivo torque production after eccentric contraction-induced injury is associated with microtubule lattice disorganization.

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The mdx mouse model as a surrogate forDuchenne muscular dystrophy

Cited by 162 publications

References 72 publications

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

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

Myofibrillar misalignment correlated to triad disappearance of mdx mouse gastrocnemius muscle probed by SHG microscopy

Microtubule binding distinguishes dystrophin from utrophin

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