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This is a In Vitro Study study.

May 13, 2026Biomedicines0 citationsOpen Access

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

YCYun ChuJiangsu University of Technology XYXinrun YuanTongji Hospital XGXiaopo GaoTongji Hospital

Key Points

This study investigates the role of PGAM2 in sepsis-induced diaphragmatic atrophy and its mechanisms.
Established murine sepsis model using cecal ligation and puncture in C57BL/6 mice.
Measured body and diaphragm weights and muscle fiber cross-sectional areas.
Evaluated PGAM2 expression using immunofluorescence and Western blotting.
Manipulated PGAM2 expression in C2C12 myotubes with siRNA and plasmid overexpression.
Assessed atrophy markers and JAK2/STAT3 pathway activation.
CLP induced approximately 38% diaphragm weight reduction and 37% decrease in muscle fiber area.
PGAM2 expression increased by approximately 105% in septic diaphragms.
PGAM2 knockdown reduced MuRF1 and MAFbx expression, decreasing myotube atrophy.
PGAM2 overexpression exacerbated myotube atrophy.
PGAM2 knockdown suppressed JAK2/STAT3 signaling pathway activation.

Abstract

Background/Objectives: Sepsis-induced systemic inflammation often leads to diaphragmatic dysfunction and muscle atrophy, contributing to impaired respiratory function. Phosphoglycerate mutase 2 (PGAM2), a key enzyme in glycolysis, plays a significant role in muscle energy metabolism but has not been previously linked to sepsis-induced diaphragmatic dysfunction. This study aims to investigate the role of PGAM2 in sepsis-induced diaphragmatic atrophy and its underlying mechanisms. Methods: A murine sepsis model was established using cecal ligation and puncture (CLP) in C57BL/6 mice. Body and diaphragm weights, along with muscle fiber cross-sectional areas, were measured. PGAM2 expression was evaluated using immunofluorescence, Western blotting, and real-time quantitative polymerase chain reaction (RT-qPCR). In vitro, C2C12 myotubes were treated with tumor necrosis factor alpha (TNF-α), and PGAM2 expression was manipulated via small interfering RNA (siRNA) knockdown and plasmid overexpression. Atrophy markers (MuRF1, MAFbx/atrogin-1) and JAK2/STAT3 pathway activation were assessed. Results: CLP induced significant diaphragmatic atrophy, as reflected by an approximately 38% reduction in diaphragm weight and an approximately 37% decrease in muscle fiber cross-sectional area compared with the sham group. In contrast, PGAM2 protein expression was increased by approximately 105% in septic diaphragms. PGAM2 expression was also significantly elevated in TNF-α-treated myotubes. PGAM2 knockdown resulted in reduced MuRF1 and MAFbx expression, attenuating myotube atrophy, while PGAM2 overexpression exacerbated atrophy. Moreover, PGAM2 knockdown suppressed activation of the JAK2/STAT3 signaling pathway. Conclusions: These findings demonstrate that PGAM2 contributes to sepsis-induced diaphragmatic atrophy through the activation of the JAK2/STAT3 signaling pathway. PGAM2 may therefore serve as a potential therapeutic target for sepsis-associated diaphragmatic dysfunction.

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