Abstract 4353558: Loss of Phosphoglucomutase-1 (PGM1) Impairs Cardiac Glycolytic flux and Mitochondrial Function in Mice.

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 - i cKO) 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-i cKO 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-i cKO 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.