Exercise Training Prevents TNF-α Induced Loss of Force in the Diaphragm of Mice

Rationale: Inflammatory cytokines like tumor necrosis factor alpha (TNF-alpha) are elevated in congestive heart failure and are known to induce the production of reactive oxygen species as well as to deteriorate respiratory muscle function. Objectives: Given the antioxidative effects of exercise training, the aim of the present study was to investigate if exercise training is capable of preventing a TNF-alpha induced loss of diaphragmatic force in mice and, if so, to elucidate the potential underlying mechanisms. Methods: Prior to intraperitoneal injection of TNF-alpha or saline, C57Bl6 mice were assigned to four weeks of exercise training or sedentary behavior. Diaphragmatic force and power generation were determined in vitro. Expression/activity of radical scavenger enzymes, enzymes producing reactive oxygen species and marker of oxidative stress were measured in the diaphragm. Main Results: In sedentary animals, TNF-alpha reduced specific force development by 42% concomitant with a 2.6-fold increase in the amount of carbonylated alpha-actin and creatine kinase. Furthermore, TNF-alpha led to an increased NAD(P) H oxidase activity in both sedentary and exercised mice whereas xanthine oxidase activity and intramitochondrial ROS production was only enhanced in sedentary animals by TNF-alpha. Exercise training prevented the TNF-alpha induced force reduction and led to an enhanced mRNA expression and activity of glutathione peroxidase. Carbonylation of proteins, in particular of alpha-actin and creatine kinase, was diminished by exercise training. Conclusion: TNF-alpha reduces the force development in the diaphragm of mice. This effect is almost abolished by exercise training. This may be a result of reduced carbonylation of proteins due to the antioxidative properties of exercise training.