Physiological role of tumor necrosis factor α in traumatic muscle injury

ABSTRACT 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.