Physiological role of tumor necrosis factor α in traumatic muscle injury

The degenerative and regenerative roles of tumor necrosis factor α (TNF-α), a pro-inflammatory cytokine with pleiotropic functions, were investigated by using TNF receptor 1 and 2 double knockout (TNFR-DKO) and TNF-α antibody neutralized mice following traumatic freeze injury to the tibialis anterior muscle. In wild-type control mice, TNF-α mRNA transcripts and protein increased following injury and gradually returned to control (uninjured) levels by 13 days. A reduction in MyoD mRNA expression occurred in TNF–α-deficient mice, although there were no visible differences in MyoD immunostaining or histological characteristics in regenerating muscles. At 5 days post-injury, the reductions in isometric strength in TNFR-DKO and TNF–α-depleted mice did not differ from that of wild-type mice but by 13 days after injury, the TNFR-DKO and TNF–αdepleted mice exhibited strength deficits twice that of wild-type mice (i.e., 27–31% vs 13%). Muscle injury was also accompanied by increased expression of interleukin-6 (IL-6), but IL–6-deficient mice demonstrated MyoD expression and recovery of isometric strength similar to that of wild-type mice. These data indicate that TNF-α is involved in the recovery of muscle function after traumatic muscle injury, and this effect might be associated with modulation of muscle regulatory genes, including MyoD.