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

Germaine Escames, Luis C. López, Víctor Tapias, Pilar Utrilla, Russel J Reiter, Ana B. Hitos, Josefa León, María I. Rodríguez, Darío Acuña-Castroviejo

Research output: Contribution to journalArticle

103 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)71-78
Number of pages8
JournalJournal of Pineal Research
Volume40
Issue number1
DOIs
StatePublished - Jan 2006

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Nitric Oxide Synthase Type II
Melatonin
Skeletal Muscle
Nitric Oxide Synthase
Sepsis
Nitric Oxide
Electron Transport
Mitochondria
Protein Isoforms
Oxidative Stress
Glutathione Disulfide
Glutathione Reductase
Glutathione Peroxidase
Lipid Peroxidation
Glutathione
Respiration

Keywords

  • Electronic transport chain
  • Melatonin
  • Mitochondrial nitric oxide synthase
  • Nitric oxide
  • Oxidative stress
  • Sepsis
  • Skeletal muscle

ASJC Scopus subject areas

  • Endocrinology

Cite this

Melatonin counteracts inducible mitochondrial nitric oxide synthase-dependent mitochondrial dysfunction in skeletal muscle of septic mice. / Escames, Germaine; López, Luis C.; Tapias, Víctor; Utrilla, Pilar; Reiter, Russel J; Hitos, Ana B.; León, Josefa; Rodríguez, María I.; Acuña-Castroviejo, Darío.

In: Journal of Pineal Research, Vol. 40, No. 1, 01.2006, p. 71-78.

Research output: Contribution to journalArticle

Escames, Germaine ; López, Luis C. ; Tapias, Víctor ; Utrilla, Pilar ; Reiter, Russel J ; Hitos, Ana B. ; León, Josefa ; Rodríguez, María I. ; Acuña-Castroviejo, Darío. / Melatonin counteracts inducible mitochondrial nitric oxide synthase-dependent mitochondrial dysfunction in skeletal muscle of septic mice. In: Journal of Pineal Research. 2006 ; Vol. 40, No. 1. pp. 71-78.
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AU - Reiter, Russel J

AU - Hitos, Ana B.

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