Sepsis decreases skeletal muscle
protein synthesis in part by impairing mTOR activity and the subsequent phosphorylation of 4E-BP1 and S6K1 thereby controlling translation initiation; however, the relative importance of changes in these two downstream substrates is unknown. The role of 4E-BP1 (and -BP2) in regulating
muscle protein synthesis was assessed in wild-type (WT) and 4E-BP1/BP2 double knockout (DKO) male mice under basal conditions and in response to
sepsis. At 12 months of age,
body weight, lean body mass and energy expenditure did not differ between WT and DKO mice. Moreover, in vivo rates of
protein synthesis in gastrocnemius, heart and liver did not differ between DKO and WT mice.
Sepsis decreased skeletal muscle
protein synthesis and S6K1 phosphorylation in WT and DKO male mice to a similar extent.
Sepsis only decreased 4E-BP1 phosphorylation in WT mice as no 4E-BP1/BP2
protein was detected in muscle from DKO mice.
Sepsis decreased the binding of
eIF4G to
eIF4E in WT mice; however, eIF4E•eIF4G binding was not altered in DKO mice under either basal or septic conditions. A comparable
sepsis-induced increase in
eIF4B phosphorylation was seen in both WT and DKO mice. eEF2 phosphorylation was similarly increased in muscle from WT septic mice and both control and septic DKO mice, compared to WT control values. The
sepsis-induced increase in muscle MuRF1 and atrogin-1 (markers of proteolysis) as well as TNFα and
IL-6 (inflammatory
cytokines)
mRNA was greater in DKO than WT mice. The
sepsis-induced decrease in myocardial and hepatic
protein synthesis did not differ between WT and DKO mice. These data suggest overall basal
protein balance and synthesis is maintained in muscle of mice lacking both 4E-BP1/BP2 and that
sepsis-induced changes in mTOR signaling may be mediated by a down-stream mechanism independent of 4E-BP1 phosphorylation and eIF4E•eIF4G binding.