The role of tumor necrosis factor-alpha (TNF-alpha) in skeletal muscle regeneration: Studies in TNF-alpha(-/-) and TNF-alpha(-/-)/LT-alpha(-/-) mice

The role of tumor necrosis factor-alpha (TNF-alpha), an important mediator of the inflammatory response after injury, was investigated in regenerating skeletal muscle. The pattern of expression of TNF-alpha. during muscle reg eneration was examined by immunohistochemistry in tissue sections of crush- injured or transplanted muscle autografts and in primary cultures of adult skeletal muscle. TNF-alpha was highly expressed in injured myofibers, infla mmatory cells, endothelial cells, fibroblasts, and mast cells. Myoblasts an d myotubes also expressed TNF-alpha in primary muscle cultures and tissue s ections. The essential role of TNF-alpha and its homologue lymphotoxin-alph a (LT-alpha) during muscle regeneration was assessed by basic histology in TNF-alpha(-/-) and TNF-alpha(-/-)/LT-alpha(-/-) mice. No difference was app arent in the onset or pattern of muscle regeneration (i.e., inflammatory re sponse, activation and fusion of myoblasts) between the two strains of null mice or between nulls and normal control mice. However, both strains of nu ll mice appeared more prone to bystander damage of host muscle and regenera tion distant from the site of injury/transplantation. Although expression o f TNF-alpha may play an important role in muscle regeneration, the studies in the null mice show that redundancy within the cytokine system (or some o ther response) can effectively compensate for the absence of TNF-alpha in v ivo.