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* Dipartimento di Fisiologia Generale ed Ambientale, Università degli Studi di Bari, I-70126 Bari, Italy;
Istituto di Anatomia Umana Normale, Policlinico, I-70124 Bari, Italy; and
Zentrum Anatomie, Abteilung Histologie, Universitaet Goettingen, D-37075 Goettingen, Germany
1Correspondence: Dipartimento di Fisiologia Generale ed Ambientale, Università degli Studi di Bari, via Amendola 165/A, I-70126 Bari, Italy. E-mail: a.frigeri{at}biologia.uniba.it
We report a detailed study of AQP4 expression in the neuromuscular
system of mdx mice. Immunocytochemical analysis performed by double
immunostaining revealed that mdx mice manifest a progressive reduction
in AQP4 at the sarcolemmal level of skeletal muscle fast fibers and
that type IIB fibers are the first to manifest this reduction in AQP4
expression. No labeling was observed in the cytoplasm of muscle fibers,
indicating that the reduction in sarcolemma staining is not associated
with an intracellular compartmentalization of mistargeted protein. By
Western blot and RT-PCR analysis, we found that whereas the total
content of AQP4 protein decreased (by 90% in adult mdx mice), mRNA
levels for AQP4 remained unchanged. A similar age-related reduction in
AQP4 expression was found in brain astrocytic end-feet surrounding
capillaries of mdx mice. Morphometric analysis performed after
immunogold electron microscopy indicated a reduction of 
85% in gold
particles (32±2/µm vs. 4.7±0.61/µm). Western blot experiments
conducted using membrane fractions from brain cortex revealed a strong
reduction (of 70%) in AQP4 protein in adult mdx mice, and RT-PCR
experiments demonstrated that the reduction was not at transcription
level. More interesting was the finding that AQP4 reduction was
associated with swelling of astrocytic perivascular processes whose
ultrastructural modifications are commonly indicated as an important
and early event in the development of brain edema. No apparent
reduction in AQP4 was found in mdx stomach and kidney. Our data provide
evidence that dystrophin deficiency in mdx mice leads to disturbances
in AQP4 assembly in the plasma membrane of fast skeletal muscle fibers
and brain astrocytic end-feet, suggesting that changes in the osmotic
equilibrium of the neuromuscular apparatus may be involved in the
pathology of muscular dystrophy.—Frigeri, A., Nicchia, G. P.,
Nico, B., Quondamatteo, F., Herken, R., Roncali, L., Svelto, M.
Aquaporin-4 deficiency in skeletal muscle and brain of dystrophic mdx
mice.
Key Words: muscular dystrophy • aquaporins • orthogonal arrays of particles • AQP4 • mdx mice • water channels
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