Summary Exercise training benefits many organ systems and offers protection against metabolic disorders such as obesity and diabetes. Using the recently identified isoform of PGC1-α (PGC1-α4) as a discovery tool, we report the identification of meteorin-like (Metrnl), a circulating factor that is induced in muscle after exercise and in adipose tissue upon cold exposure. Increasing circulating levels of Metrnl stimulates energy expenditure, improves glucose tolerance and the expression of genes associated with beige fat thermogenesis and anti-inflammatory cytokines. Metrnl stimulates an eosinophil-dependent increase in IL-4 expression and promotes alternative activation of adipose tissue macrophages, which are required for the increased expression of the thermogenic and anti-inflammatory gene programs in fat. Importantly, blocking Metrnl actions in-vivo significantly attenuates chronic cold exposure-induced alternative macrophage activation and thermogenic gene responses. Thus, Metrnl links host adaptive responses to the regulation of energy homeostasis and tissue inflammation, and has therapeutic potential for metabolic and inflammatory diseases.

Key points• A single bolus of ∼20 g of protein after a bout of resistance exercise provides a maximal anabolic stimulus during the early post-exercise recovery period (∼5 h), but the effect of various protein feeding strategies on skeletal muscle protein synthesis during an extended recovery period (12 h) is unknown.• We compared three different patterns of ingestion of 80 g of protein during 12 h recovery after resistance exercise and the associated anabolic response in human skeletal muscle. Protein was ingested in 10, 20 or 40 g feedings using a pulsed, intermediate or bolus ingestion regimen, respectively.• Our results indicate that repeated ingestion of 20 g of protein was superior for stimulating muscle protein synthesis during the 12 h experimental period.• The three dietary treatments induced differential phosphorylation of signalling proteins and changes in mRNA abundance.• This study shows that the distribution of protein intake is an important variable to promote attainment and maintenance of peak muscle mass.Abstract Quantity and timing of protein ingestion are major factors regulating myofibrillar protein synthesis (MPS). However, the effect of specific ingestion patterns on MPS throughout a 12 h period is unknown. We determined how different distributions of protein feeding during 12 h recovery after resistance exercise affects anabolic responses in skeletal muscle. Twenty-four healthy trained males were assigned to three groups (n = 8/group) and undertook a bout of resistance exercise followed by ingestion of 80 g of whey protein throughout 12 h recovery in one of the following protocols: 8 × 10 g every 1.5 h (PULSE); 4 × 20 g every 3 h (intermediate: INT); or 2 × 40 g every 6 h (BOLUS). Muscle biopsies were obtained at rest and after 1, 4, 6, 7 and 12 h post exercise. Resting and post-exercise MPS (L-[ring-13 C 6 ] phenylalanine), and muscle mRNA abundance and cell signalling were assessed. All ingestion protocols increased MPS above rest throughout 1-12 h recovery (88-148%, P < 0.02), but INT elicited greater MPS than PULSE and BOLUS (31-48%, P < 0.02). In general signalling showed a BOLUS>INT>PULSE hierarchy in magnitude of phosphorylation. MuRF-1 and SLC38A2 mRNA were differentially expressed with BOLUS. In conclusion, 20 g of whey protein consumed every 3 h was superior to either PULSE or BOLUS feeding patterns for stimulating MPS throughout the day. This study provides novel information on the effect of modulating the distribution of protein intake on anabolic responses in skeletal muscle and has the potential to maximize outcomes of resistance training for attaining peak muscle mass.

Postabsorptive rates of MPS were 27% lower in ED than EB (P Ͻ 0.001), but REX stimulated MPS to rates equal to EB. Ingestion of 15 and 30 g of protein after REX in ED increased MPS ϳ16 and ϳ34% above resting EB (P Ͻ 0.02). p70 S6K Thr 389 phosphorylation increased above EB only with combined exercise and protein intake (ϳ2-7 fold, P Ͻ 0.05). In conclusion, short-term ED reduces postabsorptive MPS; however, a bout of REX in ED restores MPS to values observed at rest in EB. The ingestion of protein after REX further increases MPS above resting EB in a dose-dependent manner. We conclude that combining REX with increased protein availability after exercise enhances rates of skeletal muscle protein synthesis during short-term ED and could in the long term preserve muscle mass. body composition; fat-free mass; myofibrillar protein synthesis; weight loss ENERGY DEFICIT (ED) can be achieved through reduced energy intake and/or increased energy expenditure and subsequently leads to loss of fat mass (FM). A reduction in FM is a goal for improved health (19, 33); however, when achieved by energy restriction alone, it typically results in the concomitant weight loss comprised of ϳ25% fat-free mass (FFM) (52), of which skeletal muscle is the main component (37,39). Given that the quality and quantity of skeletal muscle is a major determinant of whole body metabolic rate and functional capacity throughout the lifespan (25), nutritional and exercise strategies to prevent or minimize loss of FFM while losing fat mass are crucial.Pasiakos et al. (41) reported a 19% reduction in basal rates of mixed-muscle protein synthesis in young healthy males and females after 10 days of ED (ϳ500 kcal/day). In contrast, a more recent study from Pasiakos et al. (40) found no decrease in rates of resting muscle protein synthesis after 30 days of moderate ED. If a potential decrease in basal rates of muscle protein synthesis was not accompanied by a concomitant reduction in muscle protein breakdown, then ED would presumably result in a marked loss of skeletal muscle protein. Indeed, prolonged ED-induced body weight loss can be comprised of up to 60% FFM (40). In contrast, exercise has been shown to attenuate the loss of lean body tissue that typically occurs with periods of ED alone (50). However, it is currently unknown whether the anabolic effects of resistance exercise (REX) are attenuated during periods of ED.Provision of dietary amino acids increases skeletal muscle protein synthesis, an effect that is enhanced by prior REX (3, 36). To date, only one study has examined whether skeletal muscle exhibits "anabolic resistance" to exercise and protein ingestion following short-term ED (40). However, in that investigation, rates of mixed-muscle protein synthesis and not myofibrillar protein synthesis (MPS; i.e., the contractile protein fraction of muscle) were measured. Furthermore, there was no examination of the impact of exercise, and the cohort under investigation was comprised mainly of males. Hence, the primary aim of the current study was...

We determined the effects of "periodized nutrition" on skeletal muscle and whole body responses to a bout of prolonged exercise the following morning. Seven cyclists completed two trials receiving isoenergetic diets differing in the timing of ingestion: they consumed either 8 g/kg body mass (BM) of carbohydrate (CHO) before undertaking an evening session of high-intensity training (HIT) and slept without eating (FASTED), or consumed 4 g/kg BM of CHO before HIT, then 4 g/kg BM of CHO before sleeping (FED). The next morning subjects completed 2 h of cycling (120SS) while overnight fasted. Muscle biopsies were taken on day 1 (D1) before and 2 h after HIT and on day 2 (D2) pre-, post-, and 4 h after 120SS. Muscle [glycogen] was higher in FED at all times post-HIT (P < 0.001). The cycling bouts increased PGC1α mRNA and PDK4 mRNA (P < 0.01) in both trials, with PDK4 mRNA being elevated to a greater extent in FASTED (P < 0.05). Resting phosphorylation of AMPK(Thr172), p38MAPK(Thr180/Tyr182), and p-ACC(Ser79) (D2) was greater in FASTED (P < 0.05). Fat oxidation during 120SS was higher in FASTED (P = 0.01), coinciding with increases in ACC(Ser79) and CPT1 as well as mRNA expression of CD36 and FABP3 (P < 0.05). Methylation on the gene promoter for COX4I1 and FABP3 increased 4 h after 120SS in both trials, whereas methylation of the PPARδ promoter increased only in FASTED. We provide evidence for shifts in DNA methylation that correspond with inverse changes in transcription for metabolically adaptive genes, although delaying postexercise feeding failed to augment markers of mitochondrial biogenesis.

We show a similar time course for Akt-mTOR-S6K phosphorylation during the initial 60-min recovery period after divergent contractile stimuli. Conversely, enhanced phosphorylation status of proteins that promote glucose transport and glycogen synthesis only occurred after endurance exercise. Our results indicate that endurance and resistance exercise initiate translational signaling, but high-load, low-repetition contractile activity failed to promote phosphorylation of pathways regulating glucose metabolism.