Aquaporin 4 Expression in the mdx Mouse Diaphragm

Abstract

Expression of aquaporin (AQP) 4 in the surface membranes of skeletal myofibers is well established; however, its functional significance is still unknown. The alterations of AQP4 expressions in dystrophic muscles at RNA and protein levels have been reported in various dystrophic muscles such as dystrophinopathy, dysferlinopathy, and sarcoglycanopathy. We are interested in the relationship between the severity of dystrophic muscle degeneration and the expression of AQP4. Here we compared the AQP4 expression of the limb muscles with that of diaphragms in both mdx and control mice. The dystrophic muscle degeneration, such as rounding profile of cross sectional myofiber shape, dense eosin staining, central nuclei, and endomysial fibrosis in mdx mice, were more marked in diaphragms than in limb muscles. The decrease of AQP4 expression at protein level was more marked in diaphragms than in the limb muscles of mdx mice. However, the expression of AQP4 mRNA in the diaphragms of mdx mice was not reduced in comparison with limb muscles of mdx mice. The present study revealed that AQP4 expression at protein level was correlated with the severity of dystrophic changes in muscle tissues of mdx mice.

Tranilast administration reduces fibrosis and improves fatigue resistance in muscles of mdx dystrophic mice

“…Mdx mice exhibit a mild pathology with a slightly reduced lifespan (18–24 months) and functional decline of hindlimb muscles becoming evident at approximately 18 months of age [ 4 ], which is most likely a result of modifier genes in the C57BL/10 strain that can alter the effect of dystrophin loss on skeletal muscle pathology. Unlike the hindlimb muscles, the diaphragm of mdx mice undergoes progressive deterioration of muscle structure and function and is therefore a preferred muscle when examining the efficacy of potential therapeutic agents of clinical relevance [ 5 - 7 ].…”

Proteome Profiling of the Dystrophic mdx Mice Diaphragm

“…In addition to dystrophin-associated and ECM proteoforms, another highly reduced protein in the dystrophic diaphragm was aquaporin-4 (AQP4), the main water channel of the neuromuscular system. Previous studies showed markedly reduced expression of the AQP4 protein in the diaphragms of 3-month-old dystrophic mice [62], as well as in the quadriceps femoris muscle [63]. Frigeri et al [64] performed a more detailed analysis, demonstrating the reduction in AQP4 at the sarcolemmal level of skeletal-muscle fast fibers, especially type IIB fibers, and in the brain but not in the stomach and kidney.…”

Aquaporin-4 Protein Is Stably Maintained in the Hypertrophied Muscles by Functional Overload

“…The expression of AQP4 is decreased in mammalian skeletal muscle with muscular dystrophy, and thus it is suggested that AQP4 contributes to the regulation of skeletal muscle morphology [ 6 , 9 , 22 ]. However, it remains unclear whether the expression of AQP4 changes in response to morphological changes in normal skeletal muscle.…”

“…Moreover, in addition to modulating the osmotic pressure in myofibers, it has been suggested that AQP4 is involved in the regulation of myofiber energy metabolism [ 2 ]. Furthermore, as the expression of AQP4 is markedly reduced or absent in dystrophic muscles with dystrophin deficiency, it has also been suggested that AQP4-mediated water homeostasis is involved in the pathological process of muscular dystrophy [ 4 , 6 , 9 , 16 , 22 ]. On the other hand, pathologic findings, such as edema, were not detected in the morphology of skeletal muscles in AQP4 overexpressing transgenic mice [ 23 ].…”