b-Oxidation of Free Fatty Acids is Required for Maintenance of Translational Control of Protein Synthesis in Heart

The study described herein investigated the role of free fatty acids (FFAs) in the maintenance of protein synthesis in vivo in rat cardiac and skeletal muscle. Suppression of FFA b-oxidation by methyl palmoxirate caused a marked reduction in protein synthesis in the heart. The effect on protein synthesis was mediated in part by changes in the function of eukaryotic initiation factors (eIFs) involved in the initiation of mRNA translation. The guanine nucleotide exchange activity of eIF2B was repressed, phosphorylation of the a-subunit of eIF2 was enhanced, and phosphorylation of 4E-BP1 and S6K1 was reduced. Similar changes in protein synthesis and translation initiation were not observed in the gastrocnemius following treatment with methyl palmoxirate. In heart, repressed b-oxidation of FFA correlated, as demarcated by changes in ATP/AMP ratio and phosphorylation of AMP-activated kinase (AMPK), with alterations in the energy status of the tissue. Therefore, the activation state of signal transduction pathways that are responsive to the cellular energy stress represents one mechanism whereby translation initiation may be regulated in cardiac muscle.