Per citar aquest document: http://ddd.uab.cat/record/112597
Phosphofructo-1-kinase deficiency leads to a severe cardiac and hematological disorder in addition to skeletal muscle glycogenosis
García Martínez, Miguel (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i Teràpia Gènica (CBATEG))
Pujol i Altarriba, Anna (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i Teràpia Gènica (CBATEG))
Ruzo Matías, Alberto (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i Teràpia Gènica (CBATEG))
Riu Pastor, Efrén (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i Teràpia Gènica (CBATEG))
Ruberte París, Jesús (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i Teràpia Gènica (CBATEG))
Arbós Codina, Anna (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i Teràpia Gènica (CBATEG))
Serafin, Anna (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i Teràpia Gènica (CBATEG))
Albella, Beatriz (CIEMAT. Hematopoiesis and Gene Therapy Division (Madrid, Espanya))
Felíu, Juan Emilio (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i Teràpia Gènica (CBATEG))
Bosch i Tubert, Fàtima (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i Teràpia Gènica (CBATEG))

Data: 2009
Resum: Mutations in the gene for muscle phosphofructo-1-kinase (PFKM), a key regulatory enzyme of glycolysis, cause Type VII glycogen storage disease (GSDVII). Clinical manifestations of the disease span from the severe infantile form, leading to death during childhood, to the classical form, which presents mainly with exercise intolerance. PFKM deficiency is considered as a skeletal muscle glycogenosis, but the relative contribution of altered glucose metabolism in other tissues to the pathogenesis of the disease is not fully understood. To elucidate this issue, we have generated mice deficient for PFKM (Pfkm−/−). Here, we show that Pfkm−/− mice had high lethality around weaning and reduced lifespan, because of the metabolic alterations. In skeletal muscle, including respiratory muscles, the lack of PFK activity blocked glycolysis and resulted in considerable glycogen storage and low ATP content. Although erythrocytes of Pfkm−/− mice preserved 50% of PFK activity, they showed strong reduction of 2,3-biphosphoglycerate concentrations and hemolysis, which was associated with compensatory reticulocytosis and splenomegaly. As a consequence of these haematological alterations, and of reduced PFK activity in the heart, Pfkm−/− mice developed cardiac hypertrophy with age. Taken together, these alterations resulted in muscle hypoxia and hypervascularization, impaired oxidative metabolism, fiber necrosis, and exercise intolerance. These results indicate that, in GSDVII, marked alterations in muscle bioenergetics and erythrocyte metabolism interact to produce a complex systemic disorder. Therefore, GSDVII is not simply a muscle glycogenosis, and Pfkm−/− mice constitute a unique model of GSDVII which may be useful for the design and assessment of new therapies.
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès.
Document: article ; publishedVersion
Matèria: Heart ; Cardiac muscles ; Glycogens ; Skeletal muscles ; Glucose metabolism ; Red blood cells
Publicat a: PLoS Genetics, Vol. 5, Issue 8 (August 2009) , p. e1000615, ISSN 1553-7390



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