PGAM2 Regulates Sepsis-Induced Diaphragmatic Atrophy via the JAK2/STAT3 Pathway

Area of Science:

• Muscle physiology
• Cellular metabolism
• Inflammatory disease mechanisms

Background:

• Sepsis causes systemic inflammation, leading to diaphragmatic dysfunction and atrophy, impairing respiratory function.
• Phosphoglycerate mutase 2 (PGAM2), crucial for muscle energy metabolism, has not been previously linked to sepsis-induced diaphragmatic issues.

Purpose of the Study:

• To investigate the role of PGAM2 in sepsis-induced diaphragmatic atrophy.
• To elucidate the underlying molecular mechanisms involving PGAM2 in this process.

Main Methods:

• Established a murine sepsis model using cecal ligation and puncture (CLP).
• Assessed diaphragmatic atrophy markers and PGAM2 expression via Western blotting and RT-qPCR.
• Utilized in vitro C2C12 myotubes treated with TNF-α, manipulating PGAM2 levels with siRNA and plasmids to analyze atrophy markers and JAK2/STAT3 pathway activation.

Main Results:

• CLP induced significant diaphragmatic atrophy (38% reduction in weight, 37% decrease in fiber area).
• PGAM2 protein expression increased by 105% in septic diaphragms and was elevated in TNF-α-treated myotubes.
• PGAM2 knockdown attenuated myotube atrophy and suppressed JAK2/STAT3 pathway activation, while overexpression exacerbated atrophy.

Conclusions:

• PGAM2 contributes to sepsis-induced diaphragmatic atrophy via JAK2/STAT3 pathway activation.
• PGAM2 represents a potential therapeutic target for sepsis-associated diaphragmatic dysfunction.