Mouse Models of Muscular Dystrophy and Type 2 Diabetes
thesisposted on 21.10.2015, 00:00 by Nathan W. Roberts
My work has focused on the use of mouse models of human diseases to gain insight into the physiology of muscular dystrophy and Type 2 Diabetes (T2D). Muscular dystrophy is the result of mutations within key genes of the dystroglycan complex on the sarcolemmal membrane that disrupt the stability of the sarcolemmal and leads to loss of muscle function and muscle atrophy. I have focused on the mdx mouse which contains a dystrophin knock out mutation, representing the most severe form of muscular dystrophy -Duchenne muscular dystrophy. Unlike what is observed in humans, disease in the mdx mouse is not severe and it can take months for sufficient pathology to develop. A second mouse model for muscular dystrophy, the DBA2/J mouse, has been generated such that the gene for gamma sarcoglycan has been deleted and this mouse develops extensive fibrosis in its diaphragm early in life. Comparing these two models indicated that the DBA2/J knock out mouse developed more fibrosis and greater muscle membrane permeability than the mdx mouse. Histological assessment revealed overt fibrosis within the DBA2/J knock out quadriceps and diaphragm. I have also been employing a mouse model for T2D, a disease that has been continuously on the rise worldwide. There are genetic and inducible mouse T2D models, and mice that are resistant to the development of T2D have potential for the development of novel means of disease management. One such model is the MRL mouse, most studied as a model for tissue regeneration and found to express elevated pAMPK levels in its skeletal muscle. This is significant as a common treatment to promote normoglycemia in T2D, metformin, functions via the stimulation of AMPK phosphorylation in skeletal muscle and the liver. The MRL mouse was shown to be resistant to hyperglycemia following twelve weeks of a high fat diet, and I have assessed the impact of the high fat diet on the MRL heart. The obtained results indicated that the MRL heart does not hypertrophy and does not develop dysfunction after twelve weeks of the high fat diet. However the mechanisms behind this are still under investigation.