Duchenne Muscular Dystrophy (DMD) is a progressive lethal muscle disease that affects young boys. Dystrophin, absent in DMD and reduced in the milder form Becker Muscular Dystrophy (BMD), binds to several membrane-associated proteins known as dystrophin-associated proteins (DAPs). Once this critical structural link is disrupted, muscle fibers become more vulnerable to mechanical and osmotic stress. Recently, we have reported that the expression of aquaporin-4 (AQP4), a water-selective channel expressed in the sarcolemma of fast-twitch fibers and astrocyte end-feet, is drastically reduced in the muscle and brain of the mdx mouse, the animal model of DMD. In the present study, we analyzed the expression of AQP4 in several DMD/BMD patients of different ages with different mutations in the dystrophin gene. Immunofluorescence results indicate that, compared with healthy control children, AQP4 is reduced severely in all the DMD muscular biopsies analyzed and in 50% of the analyzed BMD. Western blot analysis revealed that the deficiency in sarcolemma AQP4 staining is due to a reduction in total AQP4 muscle protein content rather than to changes in immunoreactivity. Double-immunostaining experiments indicate that AQP4 reduction is independent of changes in the fiber myosin heavy chain composition. AQP4 and alpha-syntrophin analysis of BMD muscular biopsies revealed that the expression and stability of AQP4 in the sarcolemma does not always decrease when alpha-syntrophin is strongly reduced. Finally, limb-girdle muscular dystrophy biopsies and facioscapulohumeral muscular dystrophy revealed that AQP4 expression was not altered in these forms of muscular dystrophy. These experiments provide the first evidence of AQP4 reduction in a human pathology and show that this deficiency is an important feature of DMD/BMD.

Altered Aquaporin-4 expression in human muscular dystrophy: a common feaature?

FRIGERI, Antonio;NICCHIA, GRAZIA PAOLA;SVELTO, Maria
2002

Abstract

Duchenne Muscular Dystrophy (DMD) is a progressive lethal muscle disease that affects young boys. Dystrophin, absent in DMD and reduced in the milder form Becker Muscular Dystrophy (BMD), binds to several membrane-associated proteins known as dystrophin-associated proteins (DAPs). Once this critical structural link is disrupted, muscle fibers become more vulnerable to mechanical and osmotic stress. Recently, we have reported that the expression of aquaporin-4 (AQP4), a water-selective channel expressed in the sarcolemma of fast-twitch fibers and astrocyte end-feet, is drastically reduced in the muscle and brain of the mdx mouse, the animal model of DMD. In the present study, we analyzed the expression of AQP4 in several DMD/BMD patients of different ages with different mutations in the dystrophin gene. Immunofluorescence results indicate that, compared with healthy control children, AQP4 is reduced severely in all the DMD muscular biopsies analyzed and in 50% of the analyzed BMD. Western blot analysis revealed that the deficiency in sarcolemma AQP4 staining is due to a reduction in total AQP4 muscle protein content rather than to changes in immunoreactivity. Double-immunostaining experiments indicate that AQP4 reduction is independent of changes in the fiber myosin heavy chain composition. AQP4 and alpha-syntrophin analysis of BMD muscular biopsies revealed that the expression and stability of AQP4 in the sarcolemma does not always decrease when alpha-syntrophin is strongly reduced. Finally, limb-girdle muscular dystrophy biopsies and facioscapulohumeral muscular dystrophy revealed that AQP4 expression was not altered in these forms of muscular dystrophy. These experiments provide the first evidence of AQP4 reduction in a human pathology and show that this deficiency is an important feature of DMD/BMD.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11586/132759
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