title: Skeletal muscle protein synthesis and the abundance of the mRNA translation initiation repressor PDCD4 are inversely regulated by fasting and refeeding in rats.
abstract: 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 (~100 g; n = 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 (-50%) but increased PDCD4 abundance (P < 0.05); refeeding reversed these changes (P < 0.05). Consistent with these effects being regulated by S6K1, activation of this kinase was suppressed by FD (-91%, P < 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 serum-free medium, phenylalanine incorporation into proteins in cells depleted of PDCD4 more than doubled the values in cells with a normal level of PDCD4 (P < 0.0001). Thus feeding stimulates fractional protein synthesis in skeletal muscle in parallel with the reduction of the abundance of this mRNA translation inhibitor.
authors.affiliation: School of Kinesiology and Health Science, Toronto, Ontario, Canada.
authors.forename: Sana
authors.initials: S
authors.lastname: Zargar
authors.forename: Tracy S
authors.initials: TS
authors.lastname: Moreira
authors.forename: Helena
authors.initials: H
authors.lastname: Samimi-Seisan
authors.forename: Senthure
authors.initials: S
authors.lastname: Jeganathan
authors.forename: Dhanshri
authors.initials: D
authors.lastname: Kakade
authors.forename: Nushaba
authors.initials: N
authors.lastname: Islam
authors.forename: Jonathan
authors.initials: J
authors.lastname: Campbell
authors.forename: Olasunkanmi A J
authors.initials: OA
authors.lastname: Adegoke
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000502:physiology*; D002452:Cell Count; D002460:Cell Line; D004435:Eating / Q000502:physiology*; D005215:Fasting / Q000502:physiology*; D007328:Insulin / Q000097:blood; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D009124:Muscle Proteins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism; D010649:Phenylalanine / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000596:Amino Acids; D000597:Amino Acids, Branched-Chain; D051017:Apoptosis Regulatory Proteins; C519510:Crtc1 protein, rat; D007328:Insulin; D009124:Muscle Proteins; C467042:Pdcd4 protein, rat; D012333:RNA, Messenger; D014157:Transcription Factors; D010649:Phenylalanine