From the data presented here, only modest plasma levels of around 0.5 mM SMT C1100 maintained over several hours are sufficient to generate enough utrophin for substantial benefit. This strongly supports the importance of retesting new formulations of SMT C1100 in new Phase I clinical trials with a view to progressing to DMD patient trials. Aquaporin-4 is the most important water channel of the neuromuscular system. AQP4 is expressed in skeletal muscle plasmalemma, and in particular in fast-twitch fibers, in which it determines increased water permeability. In a previous work we hypothesized that AQP4, together with the endothelial AQP1, allows high water exchange between the blood and the fibers in order to regulate volume changes occurring during muscle activity which may be related to the substantial muscle swelling and intracellular osmolyte production occurring during exercise. The physiological relevance of this water channel in the skeletal muscle is supported by the fact that muscle activity modulates AQP4 expression as it is evident during disuse. Importantly, AQP4 expression is compromised in several muscle diseases, such as in hereditary muscular dystrophies, in which components of DGC are lost or strongly altered. For example, AQP4 is strongly reduced in skeletal muscle of Duchenne muscular dystrophy patients as well as in the sarcolemma of the mdx mouse, an animal model of the disease. Moreover, AQP4 down-regulation was observed in human patients affected by Limb Girdle Muscular Dystrophies, in which defects in several isoforms of sarcoglycan occur. Reduction of AQP4 expression has often been associated to a marked reduction in a1-syntrophin level, because of the close association between them. All these findings supported the idea that AQP4 water channels may be associated to dystrophin-glycoprotein complex. In order to gain better insight into the role of AQP4 in skeletal muscle, we took advantage of the AQP4-null mouse model. Previous studies performed on the same murine model have shown that AQP4 plays a pivotal role in modulating astrocytic function and preserving the blood brain barrier. Furthermore, AQP4 might be involved in the proliferation, survival, migration and neuronal differentiation of adult neural stem cells. However, no investigations have been conducted in skeletal muscle regarding the effect of the absence of AQP4 on DGC and other sarcolemma proteins. Thus, the main purpose of the present study was: a) to evaluate the effect that the lack of AQP4 has on DGC and ECM expression and LDN-193189 ALK inhibitor localization; and b) to conduct a more INCB18424 abmole bioscience global protein analysis to assess altered protein patterns in skeletal muscle of AQP4-null mice. The results presented in this study contribute to a better understanding of the relationship between AQP4 water channel, the DGC and the ECM, and suggest potential new physiological roles of this aquaporin in skeletal muscle activity.