Elevated plasma free fatty acids decrease basal protein synthesis, but not the anabolic effect of leucine, in skeletal muscle

Abstract

Lang, Charles H. Elevated plasma free fatty acids decrease basal protein synthesis, but not the anabolic effect of leucine, in skeletal muscle. Am J Physiol Endocrinol Metab 291: E666 -E674, 2006. First published May 9, 2006; doi:10.1152/ajpendo.00065.2006.-Elevations in free fatty acids (FFAs) impair glucose uptake in skeletal muscle. However, there is no information pertaining to the effect of elevated circulating lipids on either basal protein synthesis or the anabolic effects of leucine and insulin-like growth factor I (IGF-I). In chronically catheterized conscious rats, the short-term elevation of plasma FFAs by the 5-h infusion of heparin plus Intralipid decreased muscle protein synthesis by ϳ25% under basal conditions. Lipid infusion was associated with a redistribution of eukaryotic initiation factor (eIF)4E from the active eIF4E ⅐ eIF4G complex to the inactive eIF4E ⅐ 4E-BP1 complex. This shift was associated with a decreased phosphorylation of eIF4G but not 4E-BP1. Lipid infusion did not significantly alter either the total amount or phosphorylation state of mTOR, TSC2, S6K1, or the ribosomal protein S6 under basal conditions. In control rats, oral leucine increased muscle protein synthesis. This anabolic response was not impaired by lipid infusion, and no defects in signal transduction pathways regulating translation initiation were detected. In separate rats that received a bolus injection of IGF-I, lipid infusion attenuated the normal redistribution of eIF4E from the active to inactive complex and largely prevented the increased phosphorylation of 4E-BP1, eIF4G, S6K1, and S6. This IGF-I resistance was associated with enhanced Ser 307 phosphorylation of insulin receptor substrate-1 (IRS-1). These data indicate that the short-term elevation of plasma FFAs impairs basal protein synthesis in muscle by altering eIF4E availability, and this defect may be related to impaired phosphorylation of eIF4G, not 4E-BP1. Moreover, hyperlipidemia impairs IGF-I action but does not produce leucine resistance in skeletal muscle. leucine; insulin-like growth factor I; eukaryotic initiation factor 4E-binding protein-1; eukaryotic initiation factor 4G; mammalian target of rapamycin; tuberous sclerosis complex 2 IN CONTRAST TO THE EXTENSIVE LITERATURE on the relationship between circulating free fatty acids (FFAs) and glucose metabolism, there is a paucity of information pertaining to the impact of FFAs on protein metabolism. Early studies where plasma FFAs were acutely increased by infusion of Intralipid plus heparin (9) reported a generalized hypoaminoacidemia. This response demonstrates a mismatch between the rates of appearance and disappearance of amino acids and suggests that elevated plasma FFAs increase protein synthesis and/or decrease proteolysis. This protein-sparing effect of lipid was confirmed in isotope dilution studies where radiolabeled leucine was used, which concluded that increased FFA availability was inversely related to the rate of whole body proteolysis (e.g., decreased rate of leucine appearance) b...

Lipid-Induced Insulin Resistance Is Associated With an Impaired Skeletal Muscle Protein Synthetic Response to Amino Acid Ingestion in Healthy Young Men

“…Furthermore, this inability of skeletal muscle to increase protein synthesis in response to insulin and amino acid administration appeared to be partly mediated by the repression of translation initiation at the level of 4E-BP1, which is in agreement with previous studies demonstrating that elevating lipid availability in rats and cells decreases muscle protein synthesis (20,21). This is, to our knowledge, the first study to acutely induce anabolic resistance in humans by lipid administration.…”

Muscle Protein Synthesis and Balance Responsiveness to Essential Amino Acids Ingestion in the Presence of Elevated Plasma Free Fatty Acid Concentrations

“…Contrary to these observations in humans, Lang (14) has shown a decrease in muscle protein synthesis during lipid infusion in rats. In that study (14), as well as in other studies in rats (37), plasma insulin concentrations appear unaffected by the lipid infusion, whereas they increased in the present study, and similarly to what has been reported in other studies in humans (29,30). Therefore, determination of muscle protein kinetics in the presence of increased plasma insulin concentrations, secondary to increased plasma FFA concentrations, may have played a role in the present findings and given the role of insulin in regulating muscle protein turnover (16).…”

“…In humans, elevated plasma FFA concentrations decrease amino acid flux (12), and have also been associated with lower rates of protein breakdown and synthesis at the muscle (12,13). Recent mechanistic evidence from animal studies indicates that the translation initiation process of muscle protein synthesis is impaired in the presence of elevated plasma FFA concentrations (14).…”

Effects of skeletal muscle energy availability on protein turnover responses to exercise

“…Increased intracellular accumulation of lipid within skeletal muscle with human ageing is implicated in so-called 'anabolic resistance' through direct inhibition of anabolic pathways and/or activation of proinflammatory cytokines (Rivas et al, 2012;Savage et al, 2005). Results from animal studies initially demonstrated that a short-term 7-fold elevation of plasma FFA (via intralipid infusion) decreased basal rates of MPS (Lang, 2006). This attenuation was associated with decreased eIF4G but not mTOR, p70 S6K or 4E-BP1 phosphorylation, supporting recent findings showing 2 weeks of a high-fat diet preceding exercise to have little effect on mTORC1 signalling in rat skeletal muscle (Castorena et al, 2015).…”

“…As eIF4G is inhibited by rapamycin (Raught et al, 2000), it is possible that short-term or transient excess fat availability causes select defects in mTORC1 substrate targeting. To add complexity, immunoprecipitation data from Lang (2006) demonstrated that an intralipid infusion over 5 h increased the association of 4E-BP1 with eIF4E in rodent muscle, thus reducing its affinity for eIF4G. In contrast, 14 weeks of a high-fat, low-carbohydrate diet reduced rates of MPS, concomitant with attenuated Akt ( protein kinase B) and p70 S6K phosphorylation, following a 14 day functional overload stimulus in mice (Sitnick et al, 2009).…”