Melatonin counteracts inducible mitochondrial nitric oxide synthase‐dependent mitochondrial dysfunction in skeletal muscle of septic mice

Abstract

Mitochondrial nitric oxide synthase (mtNOS) produces nitric oxide (NO) to modulate mitochondrial respiration. Besides a constitutive mtNOS isoform it was recently suggested that mitochondria express an inducible isoform of the enzyme during sepsis. Thus, the mitochondrial respiratory inhibition and energy failure underlying skeletal muscle contractility failure observed in sepsis may reflect the high levels of NO produced by inducible mtNOS. The fact that mtNOS is induced during sepsis suggests its relation to inducible nitric oxide synthase (iNOS). Thus, we examined the changes in mtNOS activity and mitochondrial function in skeletal muscle of wild-type (iNOS(+/+)) and iNOS knockout (iNOS(-/-)) mice after sepsis. We also studied the effects of melatonin administration on mitochondrial damage in this experimental paradigm. After sepsis, iNOS(+/+) but no iNOS(-/-) mice showed an increase in mtNOS activity and NO production and a reduction in electron transport chain activity. These changes were accompanied by a pronounced oxidative stress reflected in changes in lipid peroxidation levels, oxidized glutathione/reduced glutathione ratio, and glutathione peroxidase and reductase activities. Melatonin treatment counteracted both the changes in mtNOS activity and rises in oxidative stress; the indole also restored mitochondrial respiratory chain in septic iNOS(+/+) mice. Mitochondria from iNOS(-/-) mice were unaffected by either sepsis or melatonin treatment. The data suggest that inducible mtNOS, which is coded by the same gene as that for iNOS, is responsible for mitochondrial dysfunction during sepsis. The results also suggest the use of melatonin for the protection against mtNOS-mediated mitochondrial failure.

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

“…The activities of MnSOD, catalase, and glutathione peroxidase, as well as mitochondrial function, were decreased in limb muscle 12 h after CLP (436). Simultaneously with remarkable inhibition of mitochondrial respiratory chain activity and ATP production, intramitochondrial oxidative stress was observed after 24 h in diaphragm and limb muscle of septic mice with a decreased ratio of oxidized (GSSG) over reduced (GSH) glutathione levels, reduced total glutathione levels, higher activity of the GSH consuming glutathione peroxidase, and lower activity of the GSH regenerating enzyme glutathione reductase (186,442,443). These disturbances did not develop in iNOS Ϫ/Ϫ mice.…”

“…Muscle injury and decreases in contractile force were (at least partially) restored or prevented when the rise in iNOS expression was prevented with dexamethasone administration or when iNOS activity was inhibited (60,61,94,182,233,427). Later studies demonstrated increased mitochondrial NOS activity in diaphragm and limb skeletal muscle of endotoxemic rats which was ascribed to an inducible (mti-NOS) rather than constitutive isoform (mtcNOS) of NOS, based on the absence of this response in iNOS Ϫ/Ϫ mice (16,186,443).…”

Role of Mitochondrial Oxidative Stress in Sepsis

“…Melatonin 5 Oxidative Medicine and Cellular Longevity administration decreased mitochondrial NOS activity and inhibition of complexes I and IV in LPS-treated rats [113]. Furthermore, the results from another study suggest that melatonin can also prevent mitochondrial damage from the inducible isoform of mitochondrial NOS in septic mice [114]. Finally, it can restore mitochondrial production of ATP [115].…”

Oral Mucositis: Melatonin Gel an Effective New Treatment

“…Its important anti-inflammatory effects include expression inhibition of iNOS/i-mtNOS, COX-2 and pro-inflammatory cytokines such as IL-1β or TNF-α. Many of these properties are attributed to the inhibition of NF-κB-dependent innate immune pathway activation [69][70], and we recently showed that melatonin blunts NLRP3 inflammasome activation under different experimental conditions [11,[71][72].…”