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Background: As spaceflight compromises skeletal muscle oxidative and aerobic work capacity, this study assessed the efficacy of resistance exercise (RE) to counteract muscle metabolic perturbations induced by 5 wk unilateral lower limb unloading (UL). Methods: There were 21 men and women (30-56 yr) who were randomly assigned to either UL with (Group, Grp; UL+RE; N = 10) or without (Grp UL; N = 11 ) concurrent RE. Iso-inertial RE comprised four sets of seven maximal coupled concentric-eccentric knee extensions executed 2-3 times per week. Percutaneous biopsies were obtained from m. vastus lateralis before and after either intervention. Levels of mRNA expression of factors regulating skeletal muscle oxidative capacity, i.e., peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1ɑ) and vascular endothelial growth factor (VEGF), and glycolytic capacity, i.e., phosphofructokinase (PFK), glycogen phosphorylase and synthase, hexokinase, and phosphorylase kinase ɑ1, were subsequently analyzed. Results: Grp UL showed decreased (36%) PGC-1ɑ expression, increased (1.5-fold) PFK expression, and a trend toward decreased VEGF post-intervention. Grp UL+RE showed no changes. Discussion: These results suggest that 5 wk unloading reduces skeletal muscle oxidative capacity and increases glycolytic enzyme activity. More importantly, only 12 bouts of high-force, low-volume resistance exercise attenuated these responses. Thus, the current resistance exercise paradigm emphasizing eccentric overload effectively counteracts unwarranted metabolic alterations induced by 5 wk unloading and may, therefore, aid in maintaining skeletal muscle integrity and endurance, and hence astronaut health and fitness during spaceflight. [ABSTRACT FROM AUTHOR]