Does utrophin expression in muscles of mdx mice during postnatal development functionally compensate for dystrophin deficiency?

doi:10.1016/0022-510X(94)90295-X

Journal of the Neurological Sciences

Volume 122, Issue 2, April 1994, Pages 162-170

https://doi.org/10.1016/0022-510X(94)90295-X Get rights and content

Abstract

We correlated utrophin expression with the physiopathological course in mdx mice. Evolution of the pathology was assessed by monitoring expression of developmental MHC in mdx mice versus control. Utrophin expression is detected by dystrophin/utrophin cross-reacting antibodies and can only be evaluated in mdx mouse muscles (in absence of dystrophin). This protein was expressed at the periphery of all myotubes and myofibers during the first postnatal week. It began declining in fast muscles before the third week and disappeared from the soleus between the 3rd and the 4th week. The decrease was concomitant with a sudden degenerative/regenerative process affecting slow muscle earlier and more massively than fast muscles. The pathological process became stable in all muscle types (except the diaphragm), with greater utrophin expression in the soleus. These results in mdx mice along with observed utrophin expression in severely affected DMD patients suggest that overexpression of utrophin is not enough to explain the stability of regenerated fibers in mdx mice.

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In mature innervated normal myofibres utrophin is restricted to the sarcolemma beneath the NMJ, and is also found at myotendinous junctions, in peripheral nerves and the vasculature (Vater et al., 1998). In developing immature myotubes and myofibres, utrophin is present around all the sarcolemma but becomes restricted to the NMJ as myofibres mature: this occurs by 3 weeks after birth in both normal and mdx mice (Pons et al., 1994; Khurana et al., 1991; Law et al., 1994). However after 3 weeks in mdx mice, in response to the acute onset of myonecrosis the utrophin protein is markedly increased in new myotubes and regenerating myofibres (Pons et al., 1994; Khurana et al., 1991; Law et al., 1994) and can remain elevated around the sarcolemma of regenerated myofibres.
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Mice, unlike humans, are also commonly analyzed as inbred strains, which can possess different intrinsic characteristics that would be expected to modify experimental results (Grounds & McGeachie, 1989; Irintchev & Wernig, 1987). Mice also have higher expression of the utrophin protein, which may compensate for a defective dystrophin (Pons, Robert, Marini, & Leger, 1994), and their satellite cells (like all mouse cells) have telomeres that are ~ 50-fold longer than a human's (Prowse & Greider, 1995). Evidence for each of these as a disease-modifying factor in mouse comes from mutant strains carrying multiple mutations: mdx/utrophin knockout mice (Grady et al., 1997) or mdx/telomerase knockout mice (Sacco et al., 2010) have a much more severe phenotype, approaching that of the human disease state.
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We previously identified a cluster of basic spectrin-like repeats in the dystrophin rod domain that binds F-actin through electrostatic interactions (Amann, K. J., Renley, B. A., and Ervasti, J. M. (1998) J. Biol. Chem. 273, 28419–28423). Because of the importance of actin binding to the presumed physiological role of dystrophin, we sought to determine whether the autosomal homologue of dystrophin, utrophin, shared this rod domain actin binding activity. We therefore produced recombinant proteins representing the cluster of basic repeats of the dystrophin rod domain (DYSR11–17) or the homologous region of the utrophin rod domain (UTROR11–16). Although UTROR11–16 is 64% similar and 41% identical to DYSR11–17, UTROR11–16 (pI = 4.86) lacks the basic character of the repeats found in DYSR11–17 (pI = 7.44). By circular dichroism, gel filtration, and sedimentation velocity analysis, we determined that each purified recombinant protein had adopted a stable, predominantly α-helical fold and existed as a highly soluble monomer. DYSR11–17 bound F-actin with an apparentK _d of 7.3 ± 1.3 μm and a molar stoichiometry of 1:5. Significantly, UTROR11–16 failed to bind F-actin at concentrations as high as 100 μm. We present these findings as further support for the electrostatic nature of the interaction of the dystrophin rod domain with F-actin and suggest that utrophin interacts with the cytoskeleton in a manner distinct from dystrophin.
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Research articleDoes utrophin expression in muscles of mdx mice during postnatal development functionally compensate for dystrophin deficiency?

Abstract

J. Neurol. Sci.

J. Immunol. Methods

J. Neurol. Sci.

Dev. Biol.

Neuromusc. Dis.

Neuromusc. Dis.

Biochim. Biophys. Acta

Brain Dev.

FEBS Lett.

Biochem. Biophys. Res. Commun.

Cell

J. Neurol. Sci.

J. Neurol. Sci.

Defective myoblasts identified in DMD

Local changes in myosin types in diseased human atrial myocardium: a quantitative immunofluorescence study

Circulation

Structural changes in the early stage of Duchenne muscular dystrophy

J. Neurol. Neurosurg. Psychiat.

The mdx mouse skeletal muscle myopathy. I. A histochemical, morphometric and biochemical investigation

Neuropathol. Appl. Neurobiol.

Ultrastructure of the skeletal muscle in the X chomosome linked dystrophic mouse

Comparison with Duchenne muscular dystrophy

Acta Neuropathol.

Differences in the muscle pathology of Duchenne muscular dystrophy patients and the mdx mouse, both of wich have a lack of dystrophin

Muscle development in mdx mutant mice

Muscle Nerve

Local diversity of myosin expression in mammalian atrial muscles

Circ. Res.

Progressive deterioration of muscles in mdx mice induced by overload

Clin. Sci.

Differential expression of muscular dystrophy in diaphragm versus hind limb muscles of mdx mice

Muscle Nerve

Research article
Does utrophin expression in muscles of mdx mice during postnatal development functionally compensate for dystrophin deficiency?