We can therefore hypothesise that the hyperglycosylation of a-DG alters some aspects of basement membrane turnover. Interestingly, a defect of glycosylated dystroglycan as present in the Large mice is also associated with reduced sarcolemmal integrity and damage induced by eccentric exercise, further indicating the role of the dystroglycanlinked basal lamina to the maintenance of sarcolemmal integrity and protection of muscles from damage. The lack of obvious muscle pathology in the limb muscles and the diaphragm of old mice nevertheless suggests that this is a subtle, and subclinical defect. LARGE transgene expression and a-DG hyperglycosylation was also detected in cardiac muscle in all transgenic lines; however in this organ there was a patchy expression of the transgene. We do not know why only a subset of cardiomyocytes Tubulin Acetylation Inducer expressed the transgene. To our knowledge this is a unique observation using the pCAGGs vector, which has been used extensively in the generation of transgenic mouse lines. Increased IIH6 immunoreactivity was restricted to regions of transgene expression. Histologically, there was no difference between the transgenic hearts compared to the non transgenic littermates. When the pattern of LARGE transgene expression in the brain was studied, we demonstrated that its expression was restricted to a discrete number of cell types, including the hippocampus, cerebellum and cortex and associated primarily with neuronal cells. Unlike skeletal and cardiac muscles, however, transgene expression was not apparently associated with significant a-DG hyperglycosylation in any of the neurons. Western blotting analysis of total brain lysates confirmed what was seen at the cellular level namely that there was no a-DG hyperglycosylation. The failure to achieve a-DG hyperglycosylation in transgenic mouse brains may be due to insufficient transgene expression in this tissue, although the promoter used has been previously shown to be ubiquitously expressed. However we were able to demonstrate that the brain has the highest levels of endogenous Large expression; we therefore hypothesise that the amount of LARGE transgene expression required to bring about a fold increase in overall protein levels is much greater in brain than in skeletal and cardiac muscles, which have considerably lower levels of endogenous Large expression. While this suggests that it might be more difficult to achieve hyperglycosylation in this tissue, it should be considered that the most severe structural brain defects seen in patients are Everolimus developmental in origin and would not be helped by postnatal restoration of a-DG function.