Leucine-enriched protein feeding does not impair exercise-induced free fatty acid availability and lipid oxidation: beneficial implications for training in carbohydrate-restricted states

Given that the enhanced oxidative adaptations observed when training in carbohydrate (CHO) restricted states are potentially regulated through free fatty acid (FFA) mediated signalling and that leucine rich protein elevates muscle protein synthesis, the present study aimed to test the hypothesis that leucine enriched protein feeding enhances circulating leucine concentration but does not impair FFA availability nor whole body lipid oxidation 56 during exercise. Nine males cycled for 2 h at 70% VO2peak when fasted (PLACEBO) or having consumed a whey protein solution (WHEY) or a leucine enriched whey protein gel (GEL), administered as 22 g 1 hour pre-exercise, 11 g/h during and 22 g thirty minutes post-exercise. Total leucine administration was 14.4 g and 6.3 in GEL and WHEY, respectively. Mean plasma leucine concentrations were elevated in GEL (P= 0.001) compared 60 with WHEY and PLACEBO (375 ± 100, 272 ± 51, 146 ± 14 μmol.L-1 respectively). No differences (P= 0.153) in plasma FFA (WHEY 0.53 ± 0.30, GEL 0.45 ± 0.25, PLACEBO 0.65 ± 0.30, mmol.L-1) or whole body lipid oxidation during exercise (WHEY 0.37 ± 0.26, GEL 0.36 ± 0.24, PLACEBO 0.34 ± 0.24 g/min) were apparent between trials, despite elevated (P= 0.001) insulin in WHEY and GEL compared with PLACEBO (38 ± 16, 35 ± 16, 22 ± 11 pmol.L-1 respectively). We conclude that leucine enriched protein feeding does not impair FFA availability nor whole body lipid oxidation during exercise, thus having practical applications for athletes who deliberately train in CHO restricted states to promote skeletal muscle adaptations

Postexercise High-Fat Feeding Supresses p70S6K1 Activity in Human Skeletal Muscle.

PURPOSE: To examine the effects of reduced CHO but high post-exercise fat availability on cell signalling and expression of genes with putative roles in regulation of mitochondrial biogenesis, lipid metabolism and muscle protein synthesis (MPS). METHODS: Ten males completed a twice per day exercise model (3.5 h between sessions) comprising morning high-intensity interval (HIT) (8 x 5-min at 85% VO2peak) and afternoon steady-state (SS) running (60 min at 70% VO2peak). In a repeated measures design, runners exercised under different isoenergetic dietary conditions consisting of high CHO (HCHO: 10 CHO, 2.5 Protein and 0.8 Fat g.kg per whole trial period) or reduced CHO but high fat availability in the post-exercise recovery periods (HFAT: 2.5 CHO, 2.5 Protein and 3.5 Fat g.kg per whole trial period). RESULTS: Muscle glycogen was lower (P<0.05) at 3 (251 vs 301 mmol.kgdw) and 15 h (182 vs 312 mmol.kgdw) post-SS exercise in HFAT compared to HCHO. AMPK-α2 activity was not increased post-SS in either condition (P=0.41) though comparable increases (all P<0.05) in PGC-1α, p53, CS, Tfam, PPAR and ERRα mRNA were observed in HCHO and HFAT. In contrast, PDK4 (P=0.003), CD36 (P=0.05) and CPT1 (P=0.03) mRNA were greater in HFAT in the recovery period from SS exercise compared with HCHO. p70S6K activity was higher (P=0.08) at 3 h post-SS exercise in HCHO versus HFAT (72.7 ± 51.9 vs 44.7 ± 27 fmol.min mg). CONCLUSION: Post-exercise high fat feeding does not augment mRNA expression of genes associated with regulatory roles in mitochondrial biogenesis though it does increase lipid gene expression. However, post-exercise p70S6K1 activity is reduced under conditions of high fat feeding thus potentially impairing skeletal muscle remodelling processes

Biological evaluation of novel 6-Arylbenzimidazo [1,2-c] quinazoline derivatives as inhibitors of LPS-induced TNF- alpha secretion

This study describes the effect of novel 6-Arylbenzimidazo [1,2-c] quinazoline derivatives as tumor necrosis factor alpha (TNF-á) production inhibitors. The newly synthesized compounds were tested for their in vitro ability to inhibit the lipolysaccharide (LPS) induced TNF-á secretion in the human promyelocytic cell line HL-60. The compound 6-Phenyl-benzimidazo [1,2-c] quinazoline, coded as Gl, resulted as the most potent inhibitor and with no significant cytotoxic activity. Thus, 6-Arylbenzimidazo [1,2-c] quinazoline derivatives may have a potential as anti-inflammatory agent

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality.

Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1-/- donors. PD-L1–deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1-/- donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell–mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD