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Effect of severe short-term malnutrition on diaphragm muscle signal transduction pathways influencing protein turnover

¹Division of Pulmonary/Critical Care Medicine, Burns and Allen Research Institute, Cedars-Sinai Medical Center, ²David Geffen School of Medicine, University of California Los Angeles, Los Angeles; ³Section of Neurobiology, Physiology, and Behavior, College of Biological Sciences, and ⁴Department of Physiology and Membrane Biology, University of California Davis School of Medicine, Davis, California

Submitted 28 September 2005 ; accepted in final form 6 February 2006

The aim of this study was to evaluate the effect of nutritional deprivation (ND) on signal transduction pathways influencing the translational apparatus in the diaphragm muscle. Male rats were divided into two groups: 1) 20% of usual food intake for 4 days (ND) with water provided at libitum and 2) free-eating control (Ctl). Total protein and RNA were extracted from the diaphragm. Insulin-like growth factor I mRNA was analyzed by RT-PCR. Protein analyses of key cytoplasmic proteins for three signaling pathways deemed important in influencing protein turnover [phosphatidylinositol 3-kinase- Akt-mammalian target of rapamycin, P13K/Akt/glycogen synthase kinase (GSK)-3, and MAPK-ERK] were performed by Western blot. Body weight decreased 30% in ND and increased 17% in Ctl animals. Diaphragm mass decreased 29% in ND animals. Muscle insulin-like growth factor I mRNA abundance was reduced 63% in ND animals. ND resulted in a 55% reduction in phosphorylated (Ser⁴⁷³) Akt. Phosphorylation of mammalian target of rapamycin at Ser²⁴⁴⁸ was reduced by 85% in ND animals. Downstream effectors important in translation initiation were also affected by ND. Phosphorylated (Thr³⁸⁹) 70-kDa ribosomal protein S6 kinase was significantly reduced (35%) by ND. ND also resulted in significant dephosphorylation of the translational repressor initiation factor 4E-binding protein 1. Phosphorylation of GSK-3 (Ser²¹) and GSK-3 (Ser⁹) was increased 55 and 45%, respectively, with ND. Phosphorylation of ERK1 (Thr²⁰²) and ERK2 (Tyr²⁰⁴), p44 and p42, respectively, was reduced 64 and 55%, respectively, with ND. Total protein concentration for all signaling intermediates of the three pathways was preserved. We conclude that short-term ND altered the phosphorylation states of key proteins of several pathways involved in protein turnover. This forms the framework for future studies aimed at identifying therapeutic targets in the management of short-term nutritionally induced cachectic states.

nutritional deprivation; muscle fiber atrophy; cachexia; mRNA translation

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