Abstract Body (Do not enter title and authors here): Background
Phosphoglucomutase 1 (PGM1) is essential for converting glucose 1-phosphate to glucose 6-phosphate, playing a pivotal role in glycolysis, glycogen metabolism, and glycosylation. PGM1 deficiency can result in a variety of clinical symptoms, including congenital malformations, hypoglycemia, hormonal imbalances, hepatopathy, and notably, severe Dilated Cardiomyopathy (DCM) and myopathy. Although oral D-galactose supplementation has shown some improvement in selected clinical abnormalities for PGM1-deficient patients, it has not been effective in alleviating severe DCM or associated myopathy. The pathophysiology of DCM and myopathy in PGM1-deficiency remains largely unknown thereby impeding the development of effective therapeutic interventions. This study aims to investigate the unresolved molecular mechanisms underlying the DCM phenotype in PGM1 deficiency.
Hypothesis
We hypothesize that impaired glucose metabolism due to PGM1-deficiency leads to early mitochondrial dysfunction characterized by disrupted TCA cycle and reduced substrate utilization.
Methods and Results
To delineate the pathophysiology of cardiac dysfunctions in PGM1-deficiency, we previously developed a cardiomyocyte-specific Pgm1 conditional knockout (Pgm1-icKO) mouse model. Four weeks post Pgm1 deletion, we observed altered steady-state levels of TCA cycle metabolites, including reduced succinate, fumarate, and aspartate. Using in vivo stable isotope tracing and mitochondrial functional assessments, we showed a compensatory increase in 13C labeling of TCA cycle intermediates 2 weeks after Pgm1 deletion, followed by a reduced malate and aspartate levels after 4 weeks. These defects were associated with a progressive decline in mitochondrial utilization of pyruvate, palmitoyl carnitine and alpha-ketoglutarate, but not succinate in Pgm1-icKO hearts. The results of our study also revealed disruption of mitochondrial respiration as early as four weeks following Pgm1-deletion. Furthermore, as early as four weeks after Pgm1 deletion, the Pgm1-icKO heart exhibited aberrant activation of protein kinase B (AKT) and mammalian target of rapamycin (mTOR) signaling. We postulate that disruption of glucose metabolism leads to cellular energy deficiency and increased metabolic stress, resulting in compensatory signaling pathways.
Conclusions
Our findings reveal metabolic dysregulation in the Pgm1-deficient heart during the development of dilated cardiomyopathy.