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DMD is caused by mutations in the dystrophin gene, which lead to the absence of the protein dystrophin or expression of a non-functional truncated protein product. About one third of DMD boys present with a significant degree of cognitive deficits. To date, the precise role of dystrophin in the CNS remains elusive. This dissertation investigated the effects of the absence of dystrophin in cerebellar Purkinje cells of the mdx mouse. A significant reduction in the amplitude of mIPSCs was found in the cerebellar Purkinje cells of mdx mice compared to littermate controls. This is consistent with the reported reduction in the number and size of GABAA receptor clusters immunoreactive for 1 subunit at the postsynaptic densities of mdx mice. Peak-scaled non-stationary noise-analysis, a quantitative assessment based on electrophysioglogical responses showed that there was significantly less number of GABAA receptors at synapses of dystrophin-deficient Purkinje cells compared to littermate controls. In addition, when gaboxadol, was added to the bath, the change in holding current was significantly enhanced in mdx mice indicating an increased in the number of peri-synaptic receptors. More importantly, the result presented here showed these peri-synaptically located GABAA receptors are functioning normally in mdx mice. These findings have important consequences for designing future pharmacological intervention, aimed at ameliorating some of the aberrant Purkinje cell functioning identified. In agreement with the gene expression finding reported by Wallis and colleagues (2004), the protein expression analysis here showed that there was no difference between littermate control and mdx mice in the expression of GABAA receptor 1 subunit in the overall membrane fraction, supporting the suggestion that it is the clustering at the synapse that is affected and not the expression of the GABAA receptor protein. Taken together, these findings provided strong evidences supporting the suggestion that dystrophin plays an important role in ion channel localization and stabilization at central synapses. If similar changes occur in the CNS in boys with DMD, it will impact on the function of neural networks and may contribute to some of the motor, behavioural and cognitive impairment apparent in many boys with DMD.

The American Cancer Society predicted that 230,480 women would be diagnosed with, and 39,520 women would die from breast cancer (BC) in the United States in 2011. While the incidence of female BC has been decreasing, BC remains the second leading cause of cancer death among women in the United States. Cancer cachexia, the cancer-related loss of muscle, affects up to 25% of BC patients and is associated with poor prognosis and decreased quality of life. Alterations to the dystrophin glycoprotein complex (DGC), a transmembrane, multi-subunit protein complex with structural and signaling roles, have been reported in mammary tumors of BC patients and skeletal muscles of cachectic cancer patients. However, this complex is most frequently studied for its role in Duchenne muscular dystrophy (DMD), a severe, progressive muscle wasting disease. Despite the similar alterations reported in these diseases, it is unclear whether alterations in the DGC in one tissue can impact the progression of disease in another. Purpose: The purpose of the studies described in this dissertation was to identify differences in body composition, energy expenditure and plasma cytokine content between the C57BL/10ScSn-Dmdmdx/J (mdx) mouse model of DMD and C57BL/10ScSnJ (BL/10) control mice and to determine whether systemic alteration of the DGC (as observed in the mdx mouse) alters the growth of E0771 murine mammary tumors. Results: There were differences in body composition and plasma cytokine profiles between mdx and BL/10 mice. We also found that, relative to controls, the tumor–induced increase in cytokines that promote invasion and metastasis was not as severe in mdx mice. Conclusions: This study revealed several differences between mdx and BL/10 mice and provides support for the suggestion that the mdx mouse may not be an accurate model of DMD. In addition, the improved cytokine profile of tumor-bearing mdx mice suggests that the acute phase of DMD may be protective against BC invasion and metastasis. Further research should confirm this effect and determine whether alterations in the DGC of the mdx mouse are directly or indirectly responsible.

Dystrophin and α-actinin-3 are two proteins found within, or in close association with, the Z-disc of skeletal muscle. Dystrophin deficiency results in the condition of Duchenne muscular dystrophy, while α-actinin-3 deficiency impairs athletic performance in sprint and power activities. Because of their location and protein interactions, and the observed effects of their deficiency in humans, they are most commonly perceived as having structural roles within muscle. This thesis attempts to gain insight into whether their roles are purely structural, or whether they may have more complex functions. Using dystrophin-deficient mdx mice, this thesis found that muscles with a greater degree of morphological deformity (fibre branching) showed a greater loss of force following eccentric (lengthening) contractions. This result indicates that evidence previously used to argue in favour of a structural role for dystrophin may have been confounded by the presence of deformed fibres. This thesis also characterised the phenotype of the Actn3 knockout mouse, a newly generated model of α-actinin-3 deficiency. The phenotype was examined at whole muscle and skinned fibre levels. Actn3 knockout muscles showed changes indicative of a shift from fast fibre-type properties towards slower fibre-type properties in the absence of α-actinin-3. These results suggest a possible role for α-actinin-3 in promoting the differentiation of fast-twitch, glycolytic properties in muscle fibres.