Aquaporin-4 expression is severely reduced in human sarcoglycanopathies and dysferlinopathies.
Aquaporin-4 (AQP4) is the major water channel expressed in fast-twitch skeletal muscle fibers. AQP4 is reduced in Duchenne and Becker Muscular Dystrophies, but not in caveolinopathies, thus suggesting an interaction with dystrophin or with members of the dystrophin-glycoprotein complex (DGC) rather than a nonspecific effect due to muscle membrane damage. To establish the role of sarcoglycans in AQP4 decrease occurring in muscular dystrophy, AQP4 expression was analyzed in muscle biopsies from patients affected by Limb Girdle Muscular Dystrophies (LGMDs) 2C-F genetically confirmed. In all the LGMD 2C-F (2alpha-, 1beta-, 2gamma-, 1delta-deficiency), AQP4 was severely decreased. This effect was associated to a marked reduction in alpha1-syntrophin levels. In control muscle AQP4 did not show a direct interaction with any of the four sarcoglycans but, it co-immunoprecipitated with alpha1-syntrophin, indicating that this modular protein may link AQP4 levels with the DGC complex. To determine whether AQP4 expression could be affected in other LGMDs due to the defect of a membrane protein not associated to the dystrophin complex, we examined AQP4 expression in 6 patients affected by dysferlin deficiency genetically confirmed. All the patients displayed a reduction of the water channel, and AQP4 expression appeared to correlate with the severity of the muscle histopathological lesions. However, differently from what observed in the sarcoglycans, alpha1-syntrophin expression was normal or just slightly reduced. These results seem to indicate an additional mechanism of regulation of AQP4 levels in muscle cells. In accordance with a specific effect of membrane muscle disorders, AQP4 protein levels were not changed in 3 mitochondrial and 3 metabolic myopathies. In conclusion, AQP4 expression and membrane localization are markedly reduced in LGMD 2B-2F. The role of AQP4 in the degenerative mechanism occurring in these diseases will be the object of our future research.
Assereto
Stefania
S
Muscular and Neurodegenerative Disease Unit, Department of Pediatrics of University of Genova, Department of Neuroscience and Rehabilitation, G. Gaslini Institute, Genoa, Italy.
Mastrototaro
Mauro
M
Stringara
Silvia
S
Gazzerro
Elisabetta
E
Broda
Paolo
P
Nicchia
Grazia Paola
GP
Svelto
Maria
M
Bruno
Claudio
C
Nigro
Vincenzo
V
Lisanti
M P
MP
Frigeri
Antonio
A
Minetti
Carlo
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D051401:Aquaporin 4 / Q000378:metabolism*; D051244:Caveolin 3 / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D000073939:Dysferlin; D016189:Dystrophin / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000172:deficiency*; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000172:deficiency*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000378:metabolism* / Q000473:pathology*; D049031:Sarcoglycans / Q000172:deficiency*
D051401:Aquaporin 4; D051244:Caveolin 3; C114839:DYSF protein, human; D000073939:Dysferlin; D016189:Dystrophin; D008565:Membrane Proteins; D009124:Muscle Proteins; D049031:Sarcoglycans