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Three weeks of caloric restriction alters protein metabolism in normal-weight young men. Am J Physiol Endocrinol Metab 289: E446-E455, 2005. First published May 3, 2005; doi:10.1152/ajpendo.00001.2005.--The effects of prolonged caloric restriction (CR) on protein kinetics in lean subjects has not been investigated previously. The purpose of this study was to test the hypotheses that 21 days of CR in lean subjects would 1) result in significant losses of lean mass despite a suppression in leucine turnover and oxidation and 2) negatively impact exercise performance. Nine young, normal-weight men [23 [+ or -] 5 y, 78.6 [+ or -] 5.7 kg, peak oxygen consumption (V[O.sub.2] peak) 45.2 [+ or -] 7.3 ml x [kg.sup.-1] x [min.sup.-1], mean [+ or -] SD] were underfed by 40% of the calories required to maintain body weight for 21 days and lost 3.8 [+ or -] 0.3 kg body wt and 2.0 [+ or -] 0.4 kg lean mass. Protein intake was kept at 1.2 g x [kg.sup.-1] x [day.sup.-1]. Leucine kinetics were measured using [alpha]-ketoisocaproic acid reciprocal pool model in the postabsorptive state during rest and 50 min of exercise (EX) at 50% of V[O.sub.2] peak. Body composition, basal metabolic rate (BMR), and exercise performance were measured throughout the intervention. At rest, leucine flux ([approximately equal to] 131 [micro]mol x [kg.sup.-1] x [h.sup.-1]) and oxidation ([R.sub.ox]; [approximately equal to] 19 [micro]mol x [kg.sup.-1] x [h.sup.-1]) did not differ pre- and post-CR. During EX, leucine flux (129 [+ or -] 6 vs. 121 [+ or -] 6) and [R.sub.ox] (54 [+ or -] 6 vs. 46 [+ or -] 8) were lower after CR than they were pre-CR. Nitrogen balance was negative throughout the intervention ([approximately equal to] 3.0g N/day), and BMR declined from 1,898 [+ or -] 262 to 1,670 [+ or -] 203 kcal/day. Aerobic performance (V[O.sub.2] peak, endurance cycling) was not impacted by CR, but arm flexion endurance decreased by 20%. In conclusion, 3 wk of caloric restriction reduced leucine flux and [R.sub.ox] during exercise in normal-weight young men. However, despite negative nitrogen balance and loss of lean mass, whole body exercise performance was well maintained in response to CR. energy intake; energy expenditure; leucine flux; exercise; nitrogen balance; lean mass