Muscular contractile failure in septic patients - Role of the inducible nitric oxide synthase pathway

Skeletal muscle failure is a frequent manifestation of sepsis that affects prognosis and rehabilitation by impairing respiration and ambulation. Anima l studies have shown that the inducible NO synthase (NOS2) is expressed in skeletal muscles during sepsis, likely affecting muscular function, by prom oting the formation of the strong oxidant peroxynitrite. In contrast, wheth er human skeletal muscle expresses a functional NOS2 in similar conditions is unknown. We studied NOS2 expression (mRNA and protein) and activity and its role in contractile function in samples from rectus abdominis muscle ob tained during surgical procedure in 16 septic patients and in 21 controls. Peroxynitrite formation was detected by immunohistochemical detection of ni trotyrosine residues. The main results of this study are as follows: (1) A significant increase in NOS2 mRNA, protein, and activity was found in muscl es from septic patients, the expression of NOS2 protein positively correlat ing with sepsis severity. (2) Contractile force was significantly lower in septic than in central muscles. This phenomenon was not reverted by muscle incubation ex vivo with the NOS inhibitor L-NMMA, indicating that NO was no t involved in force reduction at the time of biopsy. (3) NOS2 expression in skeletal myocytes was strongly co-localized with nitrotyrosine, revealing muscular peroxynitrite generation during the septic process, before the mus cle was biopsied. Exposure of control muscles to an amount of peroxynitrite similar to that generated in septic muscles during the septic: process res ulted in a nonreversible reduction in force generation. These results sugge st that NOS2 could be involved in the decreased muscular force of septic pa tients via the local generation of peroxynitrite.