Submitted on August 21, 2007
Accepted on January 5, 2008
TNF-
Acts Via TNFR1 and Muscle-Derived Oxidants to Depress Myofibrillar Force in Murine Skeletal Muscle
Brian J. Hardin1, Kenneth S. Campbell1, Jeffrey D. Smith1, Sandrine Arbogast2, Jacqueline L. Smith3, Jennifer Stevenson Moylan1, and Michael B. Reid1*
1 Department of Physiology, University of Kentucky Medical Center, Lexington, Kentucky, United States
2 Federative institute of Research, Paris, Cedex 13, France
3 Livestock Disease Diagnostic Center, University of Kentucky, Lexington, Kentucky, United States
* To whom correspondence should be addressed. E-mail: michael.reid{at}uky.edu.
Tumor necrosis factor-alpha (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-1 depressed maximal force of male ICR mouse diaphragm by ~25% within 1 hr, a deficit that persisted for 48 hrs, and increased cytosolic oxidant activity (p<0.05). Pretreating animals with the antioxidant Trolox 10 mg kg-1 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 specific force. TNF effects on force are caused, at least in part, by decrements in calcium-activated force of myofibrillar proteins.
