Abstract 10580: TNF-α Induced Loss of Force in the Diaphragm of Mice is Prevented by Exercise Training
Background: Inflammatory cytokines are known to impair respiratory muscle function, e.g. in congestive heart failure. Further, TNF-α produces reactive oxygen species (ROS) and leads to irreparable damage of muscle proteins. Exercise training (E) is characterized by a distinct antioxidative capacity. Therefore, we tested the hypothesis if exercise training is capable to prevent the TNF-α induced loss of force in the diaphragm of mice.
Methods: C57Bl6 were assigned to 4 weeks of treadmill E or sedentary behaviour (S). After 4 weeks mice were randomly injected intraperitoneally with TNF-α or saline. Force was determined in diaphragm bundles using an electrostimulation protocol. Expression and activity of glutathione peroxidase (GPX) and of the NAD(P)H oxidase and protein carbonylation were measured using standard methods.
Results: TNF-α reduced force at 125 Hz in sedentary animals. E prevented this force reduction (S NaCl: 11.6±1.0, S TNF: 6.8±0.9, E NaCl: 11.2±0.8, E TNF: 10.8±1.2 N/cm², p<0.01). TNF-α led to an increased activity of NAD(P)H oxidase in both sedentary and exercised animals (S NaCl: 1.0±0.1, S TNF: 1.8±0.2, E NaCl: 1.1±0.2, E TNF: 1.5±0.3 mU/mg, p=0.01). Carbonylated proteins as a marker of oxidative stress were only elevated under the influence of TNF-α in sedentary animals, whereas E prevented the TNF-α induced increase in carbonylated proteins. TNF-α induced loss in muscle force correlated with the total amount of carbonylated proteins (r=-0.62, p<0.05). TNF-α led to an increased carbonylation of alpha-actin (by ∼400%) and creatine kinase (by ∼500%), whereas E again prevented the TNF-α induced increase The mRNA expression and activity of GPX were enhanced by E (mRNA: S NaCl: 42.5±17.5, S TNF: 63.4±15.4, E NaCl: 179±39.2, E TNF: 190±55.6 arb. units, p<0.01; activity: S NaCl: 19.3±2.5, S TNF: 25.0±2.4, E NaCl: 31.0±2.9, E TNF: 27.4±1.7 mU/mg, p=0.01).
Conclusion: TNF-α administration leads to reduced force development in the diaphragm of mice. This effect is attenuated by preconditional exercise training. This may be, at least in part, a result of reduced carbonylation of alpha-actin and creatine kinase due to an increased expression in radical scavenger enzymes resulting in a reduced ROS concentration.
- © 2011 by American Heart Association, Inc.