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Nutrient regulation of PKC is mediated by leucine, not insulin, in skeletal muscle

¹Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine Hershey; ²Department of Biology, Lebanon Valley College, Annville; and ³Division of Allergy and Immunology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania

Submitted 30 December 2004 ; accepted in final form 5 May 2005

Nutrients enhance signaling pathways involved in skeletal muscle growth through an increased rate of protein synthesis. These studies have led to an understanding of the potential role of the mammalian target of rapamycin (mTOR) in this process. However, activation of mTOR cannot account for all the stimulatory effects of nutrients. The purpose of these experiments was to examine the effect of nutrients on the cellular distribution and activation state of novel PKC isoforms (PKC and PKC) in the gastrocnemius of rats by use of modification state-dependent phosphopeptide-specific antibodies. The phosphorylation of PKC on the catalytic domain autophosphorylation site (Ser⁷²⁹) was elevated during feeding and then returned to basal levels when the feeding period ended. Meal feeding augmented the phosphorylation of the downstream effectors of mTOR, namely S6K1 and 4E-BP1. In contrast, the phosphorylation of PKC on either the catalytic domain autophosphorylation site (Ser⁶⁴³) or activation loop site (Thr⁵⁰⁵) was unaffected. Similar results were obtained when animals were given leucine either acutely via gavage or chronically by dietary supplementations. The effect of leucine was not mimicked by injecting animals with insulin but could be induced by gavage with norleucine, a structural analog of leucine that does not increase plasma insulin concentration. Thus rises in insulin secondary to meal intake or leucine gavage are probably not responsible for increased phosphorylation of PKC in response to meal feeding. Elevating the leucine concentration stimulated the phosphorylation of PKC in gastrocnemius from perfused hindlimb and caused a shift in the distribution of PKC from the membrane fraction to the cytosolic fraction. The results indicate that leucine leads to an activation (autophosphorylation) and subcellular redistribution of PKC, but not PKC, in gastrocnemius both in vivo and in vitro. Furthermore, activation of the mTOR signaling pathway above basal conditions does not appear to be necessary to induce phosphorylation or translocation of PKC, suggesting that multiple signaling pathways become activated with leucine.

amino acids; gastrocnemius; protein kinase C isoforms; ribosomal protein S6 kinase-1; eukaryotic initiation factor 4E-binding protein-1

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