TNF-α acts via TNFR1 and muscle-derived oxidants to depress myofibrillar force in murine skeletal muscle

Brian J. Hardin, Kenneth S. Campbell, Jeffrey D. Smith, Sandrine Arbogast, Jacqueline Smith, Jennifer S. Moylan, Michael B. Reid

Research output: Contribution to journalArticlepeer-review

122 Scopus citations

Abstract

Tumor necrosis factor-α (TNF) diminishes specific force of skeletal muscle. To address the mechanism of this response, we tested the hypothesis that TNF acts via the type 1 (TNFR1) receptor subtype to increase oxidant activity and thereby depress myofibrillar function. Experiments showed that a single intraperitoneal dose of TNF (100 μg/kg) increased cytosolic oxidant activity (P < 0.05) and depressed maximal force of male ICR mouse diaphragm by ∼25% within 1 h, a deficit that persisted for 48 h. Pretreating animals with the antioxidant Trolox (10 mg/kg) lessened oxidant activity (P < 0.05) and abolished contractile losses in TNF-treated muscle (P < 0.05). Genetic TNFR1 deficiency prevented the rise in oxidant activity and fall in force stimulated by TNF; type 2 TNF receptor deficiency did not. TNF effects on muscle function were evident at the myofibrillar level. Chemically permeabilized muscle fibers from TNF-treated animals had lower maximal Ca2+-activated force (P < 0.02) with no change in Ca2+ sensitivity or shortening velocity. We conclude that TNF acts via TNFR1 to stimulate oxidant activity and depress specific force. TNF effects on force are caused, at least in part, by decrements in function of calcium-activated myofibrillar proteins.

Original languageEnglish
Pages (from-to)694-699
Number of pages6
JournalJournal of Applied Physiology
Volume104
Issue number3
DOIs
StatePublished - Mar 2008

Keywords

  • Cytokine
  • Diaphragm
  • Oxidative stress
  • Respiratory muscle
  • Weakness

ASJC Scopus subject areas

  • General Medicine

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