Signaling pathways initiated by β-hydroxy-β-methylbutyrate to attenuate the depression of protein synthesis in skeletal muscle in response to cachectic stimuli

Author:

Eley Helen L.,Russell Steven T.,Baxter Jeffrey H.,Mukerji Pradip,Tisdale Michael J.

Abstract

To investigate the mechanism by which β-hydroxy-β-methylbutyrate (HMB) attenuates the depression of protein synthesis in the skeletal muscle of cachectic mice, a study has been carried out in murine myotubes in the presence of proteolysis-inducing factor (PIF). PIF inhibited protein synthesis by 50% within 4 h, and this was effectively attenuated by HMB (25–50 μM). HMB (50 μM) alone stimulated protein synthesis, and this was attenuated by rapamycin (27 nM), an inhibitor of mammalian target of rapamycin (mTOR). Further evidence for an involvement of this pathway was shown by an increased phosphorylation of mTOR, the 70-kDa ribosomal S6 kinase (p70S6k), and initiation factor 4E-binding protein (4E-BP1) and an increased association of eukaryotic initiation factor 2 (eIF4E) with eIF4G. PIF alone induced a transient (1–2 h) stimulation of phosphorylation of mTOR and p70S6k. However, in the presence of HMB, phosphorylation of mTOR, p70S6k, and 4E-BP1 was increased, and inactive 4E-BP1-eIF4E complex was reduced, whereas the active eIF4G·eIF4E complex was increased, suggesting continual stimulation of protein synthesis. HMB alone reduced phosphorylation of elongation factor 2, but this effect was not seen in the presence of PIF. PIF induced autophosphorylation of the double-strand RNA-dependent protein kinase (PKR), leading to phosphorylation of eIF2 on the α-subunit, which would inhibit protein synthesis. However, in the presence of HMB, phosphorylation of PKR and eIF2α was attenuated, and this was also observed in skeletal muscle of cachectic mice administered HMB (0.25 g/kg). These results suggest that HMB attenuates the depression of protein synthesis by PIF in myotubes through multiple mechanisms.

Publisher

American Physiological Society

Subject

Physiology (medical),Physiology,Endocrinology, Diabetes and Metabolism

Reference44 articles.

1. Orally Administered Leucine Stimulates Protein Synthesis in Skeletal Muscle of Postabsorptive Rats in Association with Increased eIF4F Formation

2. Leucine Stimulates Translation Initiation in Skeletal Muscle of Postabsorptive Rats via a Rapamycin-Sensitive Pathway

3. Ashford AJ, Pain VM. Effect of diabetes on the rates of synthesis and degradation of ribosomes in rat muscle and liver in vivo. J Biol Chem 261: 4059–4065, 1986.

4. Avruch J, Belham QP, Weng K, Hara K, Yonezawa K. The p70S6k kinase integrates nutrient and growth signals to control translational capacity. Prog Mol Subcell Biol 76: 115–154, 2001.

5. Bibby MC, Double JA, Ali SA, Fearon KCH, Brennan RA, Tisdale MJ. Characterisation of a transplantable adenocarcinoma of the mouse colon producing cachexia in recipient animals. J Natl Cancer Inst 78: 539–546, 1987.

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3