Duchenne muscular dystrophy (DMD) is an X-linked genetic disease that affects 1 in 5,000 males. Skeletal muscle wasting occurs early in childhood, while cardiac involvement does not typically surface until a decade later. There is currently no method for predicting which patients will develop cardiomyopathy. The molecular reasons for the differences in timing and progression of cardiac dysfunction compared to skeletal dysfunction are unknown.
We used miscroarrays to compare the two tissue types at different ages of disease progression.
Overall design: All dogs were used and cared for according to principles outlined in the National Research Council Guide for the Care and Use of Laboratory Animals. Dogs were housed at the University of North Carolina at Chapel Hill. Affected dogs were identified based on dramatic elevation of serum creatine kinase (CK) and genotyped for confirmation. A total of 15 animals were included in the study: 3 young GRMD dogs (6-7.5 months), 3 older GRMD dogs (12-13 months), 6 age-matched wild type control animals, and 3 GRMD dogs of advanced age (47, 52, and 93 months-old). From a physiologic standpoint, the first year of a golden retriever’s life is analogous to the first 20 years of a human’s [21]. Thus, by dividing these ages into quartiles, 6 and 12 golden retriever months would equate to 10 and 20 human years. The natural disease course of GRMD tends to parallel DMD up to 6 months, with an onset of debilitating weakness and postural changes in both conditions. With this said, dogs with GRMD typically do not have overt clinical cardiac disease until 2 years of age or considerably later [20], well beyond their onset of skeletal muscle involvement and consistent with the relative delayed onset of cardiomyopathy in human DMD. The medial head of the gastrocnemius (MHG) and left ventricular (LV) free wall [17, 22] tissue samples were removed at necropsy, snap frozen in a Freon substitute, cooled in liquid nitrogen, stored at -80o C, and shipped in cryovials to Vanderbilt for analysis. Serum samples collected by venipuncture near the time of necropsy (either 6 or 12 months) and an earlier time point (generally 4-6 weeks), stored in cryovials at -80o C, were also shipped to Vanderbilt.
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