Endogenous peroxynitrite mediates mitochondrial dysfunction in rat diaphragm during endotoxemia

Area of Science:

• Physiology
• Biochemistry
• Pathology

Background:

• Inducible nitric oxide synthase (iNOS) in the diaphragm contributes to muscle contractile failure during endotoxemia.
• The role of nitric oxide (NO) in endotoxemia-induced muscle dysfunction and its relation to cellular oxidative pathways requires further investigation.

Purpose of the Study:

• To investigate the link between NO, cellular oxidative pathways, and diaphragmatic contractile failure during endotoxemia.
• To determine the impact of NO on mitochondrial function and oxidative stress in the diaphragm.

Main Methods:

• Rats were induced with endotoxemia using E. coli lipopolysaccharide (LPS).
• Diaphragm iNOS expression, NO levels, hydrogen peroxide (H(2)O(2)) production, and mitochondrial function were assessed.
• Mitochondrial protein nitration and diaphragmatic force were measured.
• The effect of the NOS inhibitor L-NMMA was evaluated.

Main Results:

• LPS-induced endotoxemia increased diaphragm iNOS, NO, and H(2)O(2) levels.
• Elevated NO impaired mitochondrial function, evidenced by increased H(2)O(2) and decreased phosphorylating capacity.
• Mitochondrial protein nitration and reduced diaphragmatic force were observed.
• L-NMMA administration attenuated mitochondrial dysfunction and improved diaphragmatic force.

Conclusions:

• Increased NO during endotoxemia leads to mitochondrial dysfunction via peroxynitrite formation.
• Impaired mitochondrial function contributes to diaphragmatic contractile failure in endotoxemia.
• Targeting NO synthesis may be a therapeutic strategy for sepsis-induced muscle dysfunction.