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 13C6-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.