Decrements in muscle strength as a result of prolonged bed rest are well defined, but little is known about potential countermeasures for preventing loss of strength under this condition. The purpose of this study was to determine whether testosterone administration would preserve protein balance and muscle strength during prolonged bed rest. Ten healthy men (age, 36 +/- 2 yr; height, 177.2 +/- 3.4 cm; weight, 80.5 +/- 3.9 kg; mean +/- SE) were admitted to our in-patient metabolic unit. After a 1-week ambulatory run-in period, each subject was confined to bed for 28 days at 6 degree head-down tilt while receiving a daily oral dose of T3 (50 microg/day). During the bed rest/T3 period, six of the men were randomized to receive testosterone enanthate by i.m. injection (T; 200 mg/week) while four received placebo in a double blind fashion. Nitrogen balance was determined throughout, and whole body [13C]leucine kinetics were assessed at baseline and on day 26 of bed rest. Before bed rest and on the third day of reambulation, the muscle strength of the knee extensors and flexors and shoulder extensors and flexors was determined at 60 degrees/s on a Cybex isokinetic dynamometer. Despite improved [13C]leucine kinetics and maintenance of nitrogen balance and lean body mass in T-treated subjects, little preservation of muscle strength, particularly in the knee extensors, was noted. Muscle strength [reported as the best work repetition in foot-pounds (FtLb)] for right knee extensors declined (P = 0.011) similarly in both groups; from 165 +/- 15 to 126 +/- 18 FtLb in T-treated men and from 179 +/- 22 to 149 +/- 13 FtLb in placebo-treated men. Overall, there was less of a decline in extension and flexion strength of the shoulder compared to the knee, with no benefit from T. These results suggest that in the absence of daily ambulatory activity, T administration will not increase or, in the case of this bed rest model, preserve muscle strength.