The present study was designed to test the hypothesis that upregulating
protein synthesis attenuates the loss of muscle mass in a model of
disuse atrophy. The studies compared the effect of unilateral hindlimb immobilization in wild-type (WT) mice and double-knockout (DKO) mice lacking the translational regulators 4E-BP1 and 4E-BP2. Immobilization-induced downregulation of
protein synthesis occurred in both groups of mice, but
protein synthesis was higher in gastrocnemius muscle from the immobilized hindlimb of fasted DKO compared with WT mice. Surprisingly, although
protein synthesis was partially elevated in DKO compared with WT mice,
atrophy occurred to the same extent in both groups of animals. This may be partially due to impaired
leucine-induced stimulation of
protein synthesis in DKO compared with WT mice due to downregulated eukaryotic
initiation factor eIF4E expression in muscle of DKO compared with WT mice. Expression of the E3
ubiquitin ligases MAFbx and MuRF-1 mRNAs and total
protein ubiquitylation was upregulated in the immobilized compared with the nonimmobilized hindlimb of both WT and DKO mice, with little difference in the magnitude of the upregulation between genotypes. Analysis of newly synthesized
proteins revealed downregulation of several glycolytic
enzymes in the gastrocnemius of DKO mice compared with WT mice, as well as in the immobilized compared with the nonimmobilized hindlimb. Overall, the results suggest that the elevated rate of
protein synthesis during hindlimb immobilization in fasted DKO mice is insufficient to prevent disuse-induced
muscle atrophy, probably due to induction of compensatory mechanisms including downregulation of
eIF4E expression.NEW & NOTEWORTHY Basal rates of
protein synthesis are elevated in skeletal muscle in the immobilized leg of mice lacking the translational repressors, 4E-BP1 and 4E-BP2 (knockout mice), compared with wild-type mice. However, disuse-induced
muscle atrophy occurs to the same extent in both wild-type and knockout mice suggesting that compensatory mechanisms are induced that overcome the upregulation of
muscle protein synthesis. Proteomic analysis revealed that mRNAs encoding several glycolytic
enzymes are differentially translated in wild-type and knockout mice.