. Skeletal muscle protein synthesis and the abundance of the mRNA translation initiation repressor PDCD4 are inversely regulated by fasting and refeeding in rats. Am J Physiol Endocrinol Metab 300: E986 -E992, 2011. First published March 15, 2011; doi:10.1152/ajpendo.00642.2010.-Optimal skeletal muscle mass is vital to human health, because defects in muscle protein metabolism underlie or exacerbate human diseases. The mammalian target of rapamycin complex 1 is critical in the regulation of mRNA translation and protein synthesis. These functions are mediated in part by the ribosomal protein S6 kinase 1 (S6K1) through mechanisms that are poorly understood. The tumor suppressor programmed cell death 4 (PDCD4) has been identified as a novel substrate of S6K1. Here, we examined 1) the expression of PDCD4 in skeletal muscle and 2) its regulation by feed deprivation (FD) and refeeding. Male rats (ϳ100 g; n ϭ 6) were subjected to FD for 48 h; some rats were refed for 2 h. FD suppressed muscle fractional rates of protein synthesis and Ser 67 phosphorylation of PDCD4 (Ϫ50%) but increased PDCD4 abundance (P Ͻ 0.05); refeeding reversed these changes (P Ͻ 0.05). Consistent with these effects being regulated by S6K1, activation of this kinase was suppressed by FD (Ϫ91%, P Ͻ 0.05) but was increased by refeeding. Gavaging rats subjected to FD with a mixture of amino acids partially restored muscle fractional rates of protein synthesis and reduced PDCD4 abundance relative to FD. Finally, when myoblasts were grown in amino acid-and serumfree medium, phenylalanine incorporation into proteins in cells depleted of PDCD4 more than doubled the values in cells with a normal level of PDCD4 (P Ͻ 0.0001). Thus feeding stimulates fractional protein synthesis in skeletal muscle in parallel with the reduction of the abundance of this mRNA translation inhibitor. programmed cell death 4; protein metabolism; ribosomal protein S6 kinase; mRNA translation; mammalian target of rapamycin complex 1 OPTIMAL SKELETAL MUSCLE MASS AND METABOLISM are critical to the regulation of whole body substrate homeostasis and health. Indeed, in several diseases, including obesity, diabetes, and cancer, defects in muscle metabolism underlie or exacerbate the metabolic outcomes (21,24,41).The growth factor-and nutrient-sensitive kinase complex mammalian target of rapamycin complex 1 (mTORC1) is now recognized as a master regulator of skeletal muscle mass (6,7,42,43). Upon activation, this complex phosphorylates two principal substrates, the ribosomal S6 protein kinase 1 (S6K1) and the eukaryotic initiation factor (eIF)4E-binding protein 1 (4E-BP1) (20,40). Phosphorylation of S6K1 leads to its activation, whereas 4E-BP1, an inhibitor of cap-dependent mRNA translation initiation, is inhibited by phosphorylation. S6K1 mediates the growth-promoting action of mTORC1, whereas inhibition of 4E-BP1 increases cell proliferation (9, 16).S6K1 is critical to the regulation of skeletal muscle mass because mice lacking this enzyme have reduced muscle mass (3, 38). In several stu...

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