Enfermedad de McArdle : generación de un modelo de músculo esquelético humano basado en el uso de iPSCs
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2023
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18/05/2023
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Universidad Complutense de Madrid
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La enfermedad de McArdle es una enfermedad rara de herencia autosómica recesiva, que afecta a 1 de cada 100.000 personas en la población. Se engloba dentro de las patologías conocidas como enfermedades de almacenamiento de glucógeno, o glucogenosis, que son producidas por el déficit de alguna de las enzimas implicadas en el metabolismo de síntesis o degradación del glucógeno. En concreto, la enfermedad de McArdle, o glucogenosis tipo V, se produce por mutaciones en el gen PYGM que codifica para la glucógeno fosforilasa de músculo omiofosforilasa. Esta enzima cataliza el primer paso de la ruta de degradación del glucógeno, por lo que los pacientes con la enfermedad de McArdle presentan una incapacidad para degradar el glucógeno en el músculo que se manifiesta en una marcada intolerancia al ejercicio con calambres, mialgias, contracturas o incluso rabdomiolisis y mioglobinuria en episodios más graves. En la actualidad no existe ningún tratamiento para la enfermedad de McArdle y las recomendaciones van dirigidas a prevenir y mitigar los síntomas de la enfermedad mediante la práctica de ejercicio moderado o la nutrición. Existe una gran variabilidad entre las variantes patogénicas encontradas en el gen PYGM que producen la enfermedad y los modelos de enfermedad disponibles hasta la fecha son limitados y no son útiles para llevar a cabo cribados farmacológicos de alto rendimiento. La presente tesis doctoral tiene como objetivo principal la generación de un modelo de músculo esquelético humano de la enfermedad de McArdle, el principal tipo celular afectado en estos pacientes, utilizando la tecnología de las células madre pluripotentes inducidas (iPSCs).
McArdle disease is a rare autosomal recessive disease that affects 1 in every 100.000people in the population. It is part of a group of diseases known as glycogen storage diseases, which are caused by a deficiency of one of the enzymes involved in the metabolism of glycogensynthesis or degradation. Specifically, McArdle disease, also known as glycogen storage diseasetype V is caused by mutations in the PYGM gene that encodes for the muscle isoform of glycogenphosphorylase or myophosphorylase. This enzyme catalyses the first step of the glycogendegradation pathway, so patients with McArdle disease exhibit an inability to break downglycogen in muscle, which manifests as a marked exercise intolerance with cramps, myalgias,contractures or even rhabdomyolysis and myoglobinuria in more severe episodes. There iscurrently no treatment for McArdle disease and recommendations are intended to prevent andmitigate the symptoms of the disease through moderate exercise or nutrition. There is greatvariability among the pathogenic variants found in the PYGM gene that cause the disease and thedisease models available to date are limited and are not useful for high-throughputpharmacological screening. The main objective of this doctoral thesis is to generate a humanskeletal muscle model, the main cell type affected in these patients, using induced pluripotentstem cells (iPSCs) technology that can be used as a platform for the search for new treatments...
McArdle disease is a rare autosomal recessive disease that affects 1 in every 100.000people in the population. It is part of a group of diseases known as glycogen storage diseases, which are caused by a deficiency of one of the enzymes involved in the metabolism of glycogensynthesis or degradation. Specifically, McArdle disease, also known as glycogen storage diseasetype V is caused by mutations in the PYGM gene that encodes for the muscle isoform of glycogenphosphorylase or myophosphorylase. This enzyme catalyses the first step of the glycogendegradation pathway, so patients with McArdle disease exhibit an inability to break downglycogen in muscle, which manifests as a marked exercise intolerance with cramps, myalgias,contractures or even rhabdomyolysis and myoglobinuria in more severe episodes. There iscurrently no treatment for McArdle disease and recommendations are intended to prevent andmitigate the symptoms of the disease through moderate exercise or nutrition. There is greatvariability among the pathogenic variants found in the PYGM gene that cause the disease and thedisease models available to date are limited and are not useful for high-throughputpharmacological screening. The main objective of this doctoral thesis is to generate a humanskeletal muscle model, the main cell type affected in these patients, using induced pluripotentstem cells (iPSCs) technology that can be used as a platform for the search for new treatments...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, leída el 18-05-2023