Elevated plasma free fatty acids decrease basal protein synthesis, but not the anabolic effect of leucine, in
1Dept. of Cellular Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA, USA. clang@psu.edu
Summary
High free fatty acids (FFAs) reduce muscle protein synthesis by affecting translation initiation. However, leucine
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Elevated free fatty acids (FFAs) are known to impair glucose uptake in skeletal muscle.
- The impact of increased circulating lipids on basal protein synthesis and the anabolic effects of leucine and insulin-like growth factor I (IGF-I) remains largely uncharacterized.
Purpose of the Study:
- To investigate the effects of short-term elevation of plasma FFAs on basal muscle protein synthesis.
- To determine whether hyperlipidemia affects the anabolic responses to leucine and IGF-I.
- To elucidate the molecular mechanisms underlying these effects on protein synthesis regulation.
Main Methods:
- Utilized chronically catheterized conscious rats for experiments.
- Induced short-term elevation of plasma FFAs using heparin plus Intralipid infusion.
- Assessed muscle protein synthesis rates and analyzed key signaling proteins involved in translation initiation (e.g., eIF4E, eIF4G, 4E-BP1, mTOR, S6K1).
- Administered leucine orally and IGF-I via bolus injection to assess anabolic responses.
Main Results:
- Short-term elevation of plasma FFAs decreased basal muscle protein synthesis by approximately 25%.
- Lipid infusion led to a redistribution of eukaryotic initiation factor (eIF)4E, decreasing its association with eIF4G and increasing association with 4E-BP1, accompanied by reduced eIF4G phosphorylation.
- Hyperlipidemia impaired the anabolic response to IGF-I, causing resistance, which was linked to enhanced Ser(307) phosphorylation of insulin receptor substrate-1 (IRS-1).
- The anabolic response to leucine was not impaired by lipid infusion, with no detected defects in relevant signal transduction pathways.
Conclusions:
- Short-term elevation of plasma FFAs impairs basal muscle protein synthesis by altering eIF4E availability and potentially through impaired eIF4G phosphorylation.
- Hyperlipidemia induces resistance to IGF-I's anabolic actions in skeletal muscle.
- Muscle's anabolic response to leucine remains intact despite elevated FFAs, suggesting differential regulation by nutrients and hormones.
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