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Absence of correlation between utrophin localization and quantity and the clinical severity in Duchenne/Becker
M Vainzof1, M R Passos-Bueno, N Man
1Departamento de Biologia, IB USP, São Paulo, Brazil.
Abstract:
While present in the surface membrane of embryonic muscle fibers, in adult normal muscle fibers, utrophin is restricted to the motor endplate and cells of blood vessel walls. However, the observation that utrophin is maintained in the extrajunctional plasma membrane in Duchenne (DMD) and in mdx muscle fibers has led to the suggestion that excess utrophin might compensate for dystrophin deficiency in the Xp21 muscular dystrophies. In order to detect an inverse correlation of utrophin presence and clinical severity, we have assessed utrophin distribution and quantity in DMD and Becker (BMD) patients of different ages and stages of clinical severity. All patients showed a positive discontinuous immunolabeling of utrophin on the sarcolemma, staining equally small and large muscle fibers, indicating that immature characteristics are maintained in such fibers. On Western blot, utrophin bands with concentrations 2- to 10-fold greater than in normal controls were detected in all DMD/BMD patients. However, no negative correlation was found between the amount of utrophin and the severity of clinical course, implying that the detectable utrophin levels in these patients did not compensate for dystrophin deficiency. In a DMD patient with growth hormone (GH) deficiency and a BMD-like clinical course, utrophin levels were comparable to the other typical DMD cases, which reinforces the hypothesis that the observed increase in utrophin is apparently not responsible for a milder clinical course in some patients with Xp21 muscular dystrophies.
Insights
Utrophin is elevated in Duchenne (DMD) and Becker muscular dystrophy (BMD) patients, but this increase does not correlate with disease severity. The excess utrophin does not appear to compensate for dystrophin deficiency in these Xp21 muscular dystrophies.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Utrophin is normally found in embryonic muscle but restricted in adults.
- Utrophin is maintained in Duchenne (DMD) and mdx muscle fibers, suggesting a potential compensatory role for dystrophin deficiency.
- Xp21 muscular dystrophies include DMD and Becker muscular dystrophy (BMD).
Purpose of the Study:
- To investigate the distribution and quantity of utrophin in DMD and BMD patients.
- To determine if increased utrophin levels correlate inversely with clinical severity in Xp21 muscular dystrophies.
- To assess if elevated utrophin compensates for dystrophin deficiency.
Main Methods:
- Immunohistochemical analysis of utrophin distribution on muscle fiber sarcolemma.
- Western blot analysis to quantify utrophin levels.
- Clinical assessment of disease severity in DMD and BMD patients.
Main Results:
- All DMD/BMD patients exhibited discontinuous utrophin immunolabeling on the sarcolemma, affecting both small and large muscle fibers.
- Western blot revealed 2- to 10-fold higher utrophin concentrations in DMD/BMD patients compared to normal controls.
- No negative correlation was observed between utrophin levels and clinical disease severity.
Conclusions:
- Elevated utrophin in DMD and BMD patients does not appear to compensate for dystrophin deficiency.
- The increased utrophin levels do not correlate with a milder clinical course in Xp21 muscular dystrophies.
- Immature muscle fiber characteristics, indicated by utrophin distribution, are maintained in these dystrophic conditions.
