Background In Duchenne muscular dystrophy (DMD) abnormal cardiac function is typically

Background In Duchenne muscular dystrophy (DMD) abnormal cardiac function is typically preceded by a decade of skeletal muscle disease. BDNF was elevated in cardiac muscle of younger GRMD but was unaltered in skeletal muscle while SPP1 was increased only in GRMD skeletal muscle. In human DMD circulating levels of BDNF were inversely correlated with ventricular function and fibrosis while SPP1 levels correlated with skeletal muscle function. Conclusion These results highlight gene expression patterns that could account for differences in cardiac and skeletal disease in GRMD. Most notably animal model-derived data were translated to DMD and support use of BDNF and SPP1 as biomarkers for cardiac and skeletal muscle involvement respectively. INTRODUCTION Duchenne muscular dystrophy (DMD) is caused WIN 55,212-2 mesylate by mutations in the gene resulting in severely reduced or absent dystrophin protein which primarily affects striated muscle function (1). DMD natural history involves progressive skeletal muscle weakness leading to loss of ambulation respiratory failure and death in the second to third decade of life (2 3 Although progressive respiratory failure was long the primary cause of DMD mortality the advent of corticosteroid therapy and non-invasive ventilatory support has increased overall survival (4) such that cardiomyopathy is now the leading cause of death (5). This has heightened the importance of early identification of cardiomyopathy. Currently prediction models incorporating advanced imaging can define abnormalities but identifying which patients will exhibit the earliest onset and rapid progression has been elusive (6-8). Despite tremendous progress in defining the WIN 55,212-2 mesylate molecular basis and pathogenesis of DMD since the identification of dystrophin (9) major gaps remain in our understanding of factors that contribute to disease progression. Animal models have been useful in studying the pathophysiologic mechanisms of DMD. The mouse the most widely used animal model of muscular dystrophy has proven invaluable in a range of pre-clinical studies. However the subtle nature of cardiac abnormalities (10) limits extrapolation to human disease (11-13). The golden retriever muscular dystrophy (GRMD) model closely approximates the progressive skeletal muscle involvement WIN 55,212-2 mesylate of human disease (12-14). Moreover onset and progression of cardiac involvement in GRMD is delayed compared with skeletal muscle (12 13 and follows a course more in line with that of human DMD (11 15 (reviewed in reference (16)). Importantly the severity of the cardiac and skeletal phenotypes varies markedly among dogs similar to humans (12 13 We used gene expression studies of GRMD cardiac and skeletal muscle to gain insights into the WIN 55,212-2 mesylate molecular pathways that might contribute to differences in onset and progression of cardiac versus skeletal muscle dysfunction. Because the GRMD model closely approximates human disease we sought to identify biomarkers of dystrophin-associated cardiomyopathy in this model and then translate our findings by studying sera from adolescent patients with DMD. Rabbit Polyclonal to RGAG1. RESULTS GRMD gene expression profiles are age-dependent and tissue-specific A total of 30 tissues (LV and MHG) from WIN 55,212-2 mesylate 15 dogs (6 normal and 9 GRMD) were grouped and analyzed according to age disease and tissue type (Table 1). For GRMD dogs versus age-matched controls there were 4 873 probes detected at disparate levels between dystrophic and wild type MHG. The vast majority (~80%) were detected for the younger animals only as shown by hierarchical clustering in Figure 1A with only 466 probes altered in GRMD dogs of both ages (Figure 1B). These results suggest that age strongly influences the transcriptional processes that drive disease progression in dystrophic skeletal muscle which is not surprising given that the clinical course of disease is strongly age-dependent. Figure 1 Microarray analysis of GRMD skeletal muscle Table 1 Overview of Gene Expression Analysis Results Dogs with GRMD typically do not have impaired ventricular function detectable by imaging or symptoms of heart failure until 2 years of age or considerably later (16) well beyond the onset of skeletal muscle involvement and consistent with the relatively delayed onset of cardiomyopathy in human DMD. Accordingly cardiac function was not assessed for the 6-12 month-old GRMD dogs. No animal had overt evidence of clinical cardiac disease. Of the three oldest.