Role of superoxide-nitric oxide interactions in the accelerated age-related loss of muscle mass in mice lacking Cu, Zn superoxide dismutase

Giorgos K. Sakellariou, Deborah Pye, Aphrodite Vasilaki, Lea Zibrik, Jesus Palomero, Tabitha Kabayo, Francis McArdle, Holly van Remmen, Arlan Richardson, James G. Tidball, Anne McArdle, Malcolm J. Jackson

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Mice lacking Cu, Zn superoxide dismutase (SOD1) show accelerated, age-related loss of muscle mass. Lack of SOD1 may lead to increased superoxide, reduced nitric oxide (NO), and increased peroxynitrite, each of which could initiate muscle fiber loss. Single muscle fibers from flexor digitorum brevis of wild-type (WT) and Sod1 -/- mice were loaded with NO-sensitive (4-amino-5-methylamino-2',7'-difluorofluorescein diacetate, DAF-FM) and superoxide-sensitive (dihydroethidium, DHE) probes. Gastrocnemius muscles were analyzed for SOD enzymes, nitric oxide synthases (NOS), and 3-nitrotyrosine (3-NT) content. A lack of SOD1 did not increase superoxide availability at rest because no increase in ethidium or 2-hydroxyethidium (2-HE) formation from DHE was seen in fibers from Sod1 -/- mice compared with those from WT mice. Fibers from Sod1 -/- mice had decreased NO availability (decreased DAF-FM fluorescence), increased 3-NT in muscle proteins indicating increased peroxynitrite formation and increased content of peroxiredoxin V (a peroxynitrite reductase), compared with WT mice. Muscle fibers from Sod1 -/- mice showed substantially reduced generation of superoxide in response to contractions compared with fibers from WT mice. Inhibition of NOS did not affect DHE oxidation in fibers from WT or Sod1 -/- mice at rest or during contractions, but transgenic mice overexpressing nNOS showed increased DAF-FM fluorescence and reduced DHE oxidation in resting muscle fibers. It is concluded that formation of peroxynitrite in muscle fibers is a major effect of lack of SOD1 in Sod1 -/- mice and may contribute to fiber loss in this model, and that NO regulates superoxide availability and peroxynitrite formation in muscle.

Original languageEnglish (US)
Pages (from-to)749-760
Number of pages12
JournalAging cell
Volume10
Issue number5
DOIs
StatePublished - Oct 2011

Keywords

  • Accelerated aging
  • Aging
  • Reactive oxygen
  • Skeletal muscle
  • Species

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Fingerprint Dive into the research topics of 'Role of superoxide-nitric oxide interactions in the accelerated age-related loss of muscle mass in mice lacking Cu, Zn superoxide dismutase'. Together they form a unique fingerprint.

Cite this