PGM1 deficiency disrupts sarcomere and mitochondrial function in a stem-cell cardiomyocyte model

Area of Science:

• Cardiology
• Metabolic Disorders
• Genetics

Background:

• Phosphoglucomutase-1 (PGM1) is crucial for glycolysis, glycogen metabolism, and glycosylation.
• Pathogenic PGM1 variants cause PGM1-congenital disorder of glycosylation (PGM1-CDG), a multisystem disorder with cardiac involvement.
• Cardiomyopathy in PGM1-CDG is not improved by galactose, suggesting a glycosylation-independent mechanism.

Purpose of the Study:

• To investigate the cardiac-specific role of PGM1 and its underlying pathomechanisms in cardiomyopathy.
• To identify potential therapeutic targets for PGM1-related cardiomyopathy.

Main Methods:

• Generated induced pluripotent stem cell-derived cardiomyocytes (iCMs) from PGM1-deficient patient fibroblasts.
• Utilized multielectrode array (MEA) recordings, untargeted (glyco)proteomics, and pathway analysis.
• Validated findings with tracer metabolomics and mitochondrial respiration assays.

Main Results:

• PGM1-deficient iCMs showed reduced beating frequency, impaired contractility, and prolonged contraction kinetics.
• Proteomic analysis revealed depletion of Z-disk components (e.g., LDB3) and mitochondrial proteins.
• Confirmed a direct interaction between PGM1 and LDB3, impacting Z-disk integrity and mitochondrial function, leading to metabolic rewiring and energy depletion.

Conclusions:

• PGM1 is essential for cardiomyocyte function, linking sarcomeric Z-disk integrity with mitochondrial metabolism.
• Mechanistic insights provide a basis for developing targeted therapies for PGM1-CDG cardiomyopathy.
• Findings may extend to other cardiomyopathies involving Z-disk dysfunction.