RESUMEN
The muscular dystrophies encompass a broad range of pathologies with varied clinical outcomes. In the case of patients carrying defects in fukutin-related protein (FKRP), these diverse pathologies arise from mutations within the same gene. This is surprising as FKRP is a glycosyltransferase, whose only identified function is to transfer ribitol-5-phosphate to α-dystroglycan (α-DG). Although this modification is critical for extracellular matrix attachment, α-DG's glycosylation status relates poorly to disease severity, suggesting the existence of unidentified FKRP targets. Here we reveal that FKRP directs sialylation of fibronectin, a process essential for collagen recruitment to the muscle basement membrane. Thus, our results reveal that FKRP simultaneously regulates the two major muscle-ECM linkages essential for fibre survival, and establishes a new disease axis for the muscular dystrophies.
Asunto(s)
Fibronectinas/metabolismo , Glicosiltransferasas/metabolismo , Distrofias Musculares/metabolismo , Distrofias Musculares/patología , Distrofia Muscular Animal/metabolismo , Distrofia Muscular Animal/patología , Pentosiltransferasa/metabolismo , Proteínas de Pez Cebra/metabolismo , Animales , Membrana Basal/metabolismo , Membrana Basal/patología , Línea Celular , Modelos Animales de Enfermedad , Técnicas de Inactivación de Genes , Glicosilación , Glicosiltransferasas/deficiencia , Glicosiltransferasas/genética , Humanos , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Distrofias Musculares/genética , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/metabolismo , Distrofia Muscular de Cinturas/patología , Distrofia Muscular Animal/genética , Mutación , Mioblastos Esqueléticos/metabolismo , Mioblastos Esqueléticos/patología , Pentosiltransferasa/deficiencia , Pentosiltransferasa/genética , Fenotipo , Pez Cebra , Proteínas de Pez Cebra/deficiencia , Proteínas de Pez Cebra/genéticaRESUMEN
This study describes the use of a shareware software package available from the National Institutes of Health for computing the fractal dimension. Specifically, when fractal analysis is used in its correct context it provides for a quantitative description of the space filling properties of two-dimensional objects. A rabbit model of post myocardial infarction is described where the cross-sectional infarct edge is reconstructed and its jaggedness determined by calculating its fractal dimension via the pixel dilation method. The fractal dimensions of the anterior and posterior lateral infarct edges were calculated to have a mean of 1.16 and 1.29, respectively. In conclusion, the fractal technique can be used to describe the complex jaggedness of the infarct edge. This case study also illustrates the fact that the complexity of an infarcted area is not uniform across the scar. For example, we found that the space filling properties of the anterior and posterior borders of a myocardial infarct can differ by more than 2-fold.
Asunto(s)
Infarto del Miocardio/patología , Miocardio/patología , Animales , Modelos Animales de Enfermedad , Fractales , Procesamiento de Imagen Asistido por Computador , Masculino , Conejos , Programas InformáticosRESUMEN
Previous studies have suggested that the jaggedness of the healed or healing infarct edge influences cardiac electrical stability. However, these findings have been based on histological observations rather than quantitative measurements. The aim of this study was to assess infarct jaggedness by calculating its fractal dimension and to examine how this influences cardiac electrical stability during late infarct healing in the rabbit. Using programmed electrical stimulation, it was found that the fractal dimension did not differ significantly in 19 rabbits that had inducible ventricular tachycardia and 16 that did not. We conclude from these studies in the mature rabbit that infarct edge jaggedness does not influence the ease with which ventricular tachycardia is induced during late myocardial infarct healing.
Asunto(s)
Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Función Ventricular/fisiología , Cicatrización de Heridas , Animales , Modelos Animales de Enfermedad , Femenino , Fractales , Procesamiento de Imagen Asistido por Computador , Masculino , Conejos , Taquicardia Ventricular/fisiopatologíaRESUMEN
Cells that are apoptotic and comprise less than 2% of the total cellular population are difficult to detect by conventional methods (i.e., DNA ladder). We discuss a new methodological technique, PCR-amplified DNA ladder, to detect very low levels of DNA fragmentation (indicative of apoptosis) in a myocardial infarct heart failure model. Results and methodology are contrasted with the traditional DNA ladder technique.