The purpose of the present study was to test the hypothesis that administration of thyroid hormone [3,5,3'-triiodo-L-thyronine (T₃)] could result in oxidation of myofibrillar proteins and, in turn, induce alterations in respiratory muscle function. Daily injection of T₃ for 21 days depressed isometric forces of diaphragm fiber bundles across a range of stimulus frequencies (1, 10, 20, 40, 75 and 100 Hz) (P < 0.05). These reductions in force production were accompanied by a remarkable increment (104%; P < 0.05) in carbonyl groups of myofibrillar proteins. In contrast, T₃ treatment has no effects on the carbonyl content in myosin heavy chain. In additional experiments, we have also tested the efficacy of carvedilol, a non-selective ₁-₂-blocker which possesses anti-oxidative properties. Treatment with carvedilol dramatically improved isometric tetanic force production at stimulus frequencies from 40 to 100 Hz (P < 0.05). Carvedilol also prevented T₃-induced contractile protein oxidation (P < 0.05). These data suggest that the oxidative modification of myofibrillar proteins may account, at least in part, for an impairment of diaphragm in hyperthyroidism.