In Vitro Skeletal Muscle Model of PGM1 Deficiency Reveals Altered Energy Homeostasis

Autor:	Federica Conte, Angel Ashikov, Rachel Mijdam, Eline G. P. van de Ven, Monique van Scherpenzeel, Raisa Veizaj, Seyed P. Mahalleh-Yousefi, Merel A. Post, Karin Huijben, Daan M. Panneman, Richard J. T. Rodenburg, Nicol C. Voermans, Alejandro Garanto, Werner J. H. Koopman, Hans J. C. T. Wessels, Marek J. Noga, Dirk J. Lefeber
Rok vydání:	2023
Předmět:	Inorganic Chemistry All institutes and research themes of the Radboud University Medical Center Organic Chemistry Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] General Medicine phosphoglucomutase 1 PGM1 deficiency PGM1 congenital disorder of glycosylation in vitro muscle model muscle energy homeostasis muscle metabolic plasticity Physical and Theoretical Chemistry Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] Molecular Biology Spectroscopy Catalysis Computer Science Applications
Zdroj:	International Journal of Molecular Sciences, 24, 9 International Journal of Molecular Sciences; Volume 24; Issue 9; Pages: 8247 International Journal of Molecular Sciences, 24
ISSN:	1422-0067
DOI:	10.3390/ijms24098247
Popis:	Contains fulltext : 292737.pdf (Publisher’s version ) (Open Access) Phosphoglucomutase 1 (PGM1) is a key enzyme for the regulation of energy metabolism from glycogen and glycolysis, as it catalyzes the interconversion of glucose 1-phosphate and glucose 6-phosphate. PGM1 deficiency is an autosomal recessive disorder characterized by a highly heterogenous clinical spectrum, including hypoglycemia, cleft palate, liver dysfunction, growth delay, exercise intolerance, and dilated cardiomyopathy. Abnormal protein glycosylation has been observed in this disease. Oral supplementation with D-galactose efficiently restores protein glycosylation by replenishing the lacking pool of UDP-galactose, and rescues some symptoms, such as hypoglycemia, hepatopathy, and growth delay. However, D-galactose effects on skeletal muscle and heart symptoms remain unclear. In this study, we established an in vitro muscle model for PGM1 deficiency to investigate the role of PGM1 and the effect of D-galactose on nucleotide sugars and energy metabolism. Genome-editing of C2C12 myoblasts via CRISPR/Cas9 resulted in Pgm1 (mouse homologue of human PGM1, according to updated nomenclature) knockout clones, which showed impaired maturation to myotubes. No difference was found for steady-state levels of nucleotide sugars, while dynamic flux analysis based on (13)C6-galactose suggested a block in the use of galactose for energy production in knockout myoblasts. Subsequent analyses revealed a lower basal respiration and mitochondrial ATP production capacity in the knockout myoblasts and myotubes, which were not restored by D-galactose. In conclusion, an in vitro mouse muscle cell model has been established to study the muscle-specific metabolic mechanisms in PGM1 deficiency, which suggested that galactose was unable to restore the reduced energy production capacity.
Databáze:	OpenAIRE
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