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

Area of Science:

• Biochemistry
• Cell Biology
• Metabolic Disorders

Background:

• Phosphoglucomutase 1 (PGM1) is crucial for energy metabolism, catalyzing glucose phosphate interconversion.
• PGM1 deficiency causes a spectrum of symptoms, including metabolic and cardiac issues, with abnormal protein glycosylation.
• D-galactose can correct some PGM1 deficiency symptoms by replenishing UDP-galactose, but its effect on muscle is unknown.

Purpose of the Study:

• To establish an in vitro muscle model for PGM1 deficiency.
• To investigate PGM1's role in muscle energy metabolism.
• To determine the effect of D-galactose on nucleotide sugars and energy production in muscle cells.

Main Methods:

• CRISPR/Cas9 genome-editing created PGM1 knockout C2C12 myoblasts.
• Analyzed nucleotide sugar levels and galactose flux using 13C6-galactose.
• Assessed basal respiration and mitochondrial ATP production in knockout myoblasts and myotubes.

Main Results:

• PGM1 knockout myoblasts showed impaired maturation and reduced basal respiration and mitochondrial ATP production.
• No differences in steady-state nucleotide sugar levels were observed between knockout and wild-type cells.
• D-galactose supplementation did not restore energy production capacity in the PGM1-deficient muscle model.

Conclusions:

• An in vitro mouse muscle cell model for PGM1 deficiency was successfully established.
• PGM1 deficiency in muscle cells leads to impaired energy metabolism and mitochondrial dysfunction.
• D-galactose is ineffective in restoring energy production in PGM1-deficient muscle cells.