Rapamycin blunts nutrient stimulation of eIF4G, but not PKCepsilon phosphorylation, in skeletal muscle.
Phosphorylation of eukaryotic initiation factor 4G (eIF4G) is hypothesized to be an important contributor to the stimulation of protein synthesis in skeletal muscle following meal feeding. The experiments reported herein examined the potential role for a rapamycin-sensitive signaling pathway in mediating the meal feeding-induced elevations in phosphorylation of eIF4G. Gastrocnemius from male Sprague-Dawley rats trained to consume a meal consisting of rat chow was sampled prior to and following 3 h of having the meal provided in the presence or absence of treatment with rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) complex 1 (TORC1). Pretreatment with rapamycin prevented the feeding-induced phosphorylation of mTOR, eIF4G, and S6K1 but only partially attenuated the shift in 4E-BP1 into the gamma-form. In contrast, the feeding-induced increase in phosphorylation of PKCepsilon was not reduced by rapamycin. Rapamycin also prevented the augmented association of eIF4G with eIF4E and the decreased association of eIF4E with 4E-BP1. Similar findings were observed in gastrocnemius from animals after oral administration of leucine. Perfusion of gastrocnemius with medium containing rapamycin partially prevented the leucine-induced increase in phosphorylation of eIF4G. Thus, rapamycin attenuated a feeding- or leucine-induced phosphorylation of eIF4G in skeletal muscle both in vivo and in situ. The latter observation implies that the effects observed with rapamycin were the result of modulation of skeletal muscle signaling mechanisms responsible for eIF4G phosphorylation.
Vary
Thomas C
TC
Department of Cellular and Molecular Physiology, Rm. C4710, Penn State University College of Medicine, H166, 500 University Drive, Hershey, PA 17033, USA. tvary@psu.edu
Anthony
Joshua C
JC
Jefferson
Leonard S
LS
Kimball
Scot R
SR
Lynch
Christopher J
CJ
D000818:Animals; D004333:Drug Administration Routes; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism*; D005502:Food; D006614:Hindlimb / Q000187:drug effects; D007930:Leucine / Q000008:administration & dosage; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology*
D039603:Eukaryotic Initiation Factor-4G; D051744:Protein Kinase C-epsilon; D007930:Leucine; D020123:Sirolimus