scholarly journals Leucine or carbohydrate supplementation reduces AMPK and eEF2 phosphorylation and extends postprandial muscle protein synthesis in rats

2011 ◽  
Vol 301 (6) ◽  
pp. E1236-E1242 ◽  
Author(s):  
Gabriel J. Wilson ◽  
Donald K. Layman ◽  
Christopher J. Moulton ◽  
Layne E. Norton ◽  
Tracy G. Anthony ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Test Meal ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Adenosine Monophosphate ◽  
Energy Status ◽  
Sprague Dawley ◽  
Translation Elongation ◽  
Cellular Energy ◽  
Mtorc1 Signaling

Muscle protein synthesis (MPS) increases after consumption of a protein-containing meal but returns to baseline values within 3 h despite continued elevations of plasma amino acids and mammalian target of rapamycin (mTORC1) signaling. This study evaluated the potential for supplemental leucine (Leu), carbohydrates (CHO), or both to prolong elevated MPS after a meal. Male Sprague-Dawley rats (∼270 g) trained to consume three meals daily were food deprived for 12 h, and then blood and gastrocnemius muscle were collected 0, 90, or 180 min after a standard 4-g test meal (20% whey protein). At 135 min postmeal, rats were orally administered 2.63 g of CHO, 270 mg of Leu, both, or water (sham control). Following test meal consumption, MPS peaked at 90 min and then returned to basal ( time 0) rates at 180 min, although ribosomal protein S6 kinase and eIF4E-binding protein-1 phosphorylation remained elevated. In contrast, rats administered Leu and/or CHO supplements at 135 min postmeal maintained peak MPS through 180 min. MPS was inversely associated with the phosphorylation states of translation elongation factor 2, the “cellular energy sensor” adenosine monophosphate-activated protein kinase-α (AMPKα) and its substrate acetyl-CoA carboxylase, and increases in the ratio of AMP/ATP. We conclude that the incongruity between MPS and mTORC1 at 180 min reflects a block in translation elongation due to reduced cellular energy. Administering Leu or CHO supplements ∼2 h after a meal maintains cellular energy status and extends the postprandial duration of MPS.

scholarly journals Systemic IL-6 regulation of eccentric contraction-induced muscle protein synthesis

2018 ◽  
Vol 315 (1) ◽  
pp. C91-C103 ◽  
Author(s):  
Justin P. Hardee ◽  
Dennis K. Fix ◽  
Xuewen Wang ◽  
Edie C. Goldsmith ◽  
Ho-Jin Koh ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Muscle Protein ◽  
Contractile Activity ◽  
Muscle Protein Synthesis ◽  
Tibialis Anterior Muscle ◽  
Eccentric Contraction ◽  
Tumor Bearing ◽  
Gp130 Receptor ◽  
Mtorc1 Signaling ◽  
Mtorc1 Activation

Systemic cytokines and contractile activity are established regulators of muscle protein turnover. Paradoxically, the IL-6 cytokine family, which shares the ubiquitously expressed membrane gp130 receptor, has been implicated in skeletal muscle’s response to both contractions and cancer-induced wasting. Although we have reported that tumor-derived cachectic factors could suppress stretch-induced protein synthesis in cultured myotubes, the ability of systemic cytokines to disrupt in vivo eccentric contraction-induced protein synthesis has not been established. Therefore, we examined whether systemic IL-6 regulates basal and eccentric contraction-induced protein synthesis through muscle gp130 signaling. Systemic IL-6 overexpression was performed for 2 wk, and we then examined basal and eccentric contraction-induced protein synthesis and mammalian target of rapamycin complex 1 (mTORC1) signaling in tibialis anterior muscle of male wild-type, muscle-specific gp130 receptor knockout, and tumor-bearing ApcMin/+ mice. Systemic IL-6 overexpression suppressed basal protein synthesis and mTORC1 signaling independently of IL-6 level, which was rescued by muscle gp130 loss. Interestingly, only high systemic IL-6 levels suppressed eccentric contraction-induced protein synthesis. Systemic IL-6 overexpression in precachectic tumor-bearing ApcMin/+ mice accelerated cachexia development, which coincided with suppressed basal and eccentric contraction-induced muscle protein synthesis. The suppression of eccentric contraction-induced protein synthesis by IL-6 occurred independently of mTORC1 activation. Collectively, these findings demonstrate that basal protein synthesis suppression was more sensitive to circulating IL-6 compared with the induction of protein synthesis by eccentric contraction. However, systemic IL-6 can interact with the cancer environment to suppress eccentric contraction-induced protein synthesis independently of mTORC1 activation.

scholarly journals Insulin Stimulates Human Skeletal Muscle Protein Synthesis via an Indirect Mechanism Involving Endothelial-Dependent Vasodilation and Mammalian Target of Rapamycin Complex 1 Signaling

2010 ◽  
Vol 24 (6) ◽  
pp. 1306-1306
Author(s):  
Kyle L. Timmerman ◽  
Jessica L. Lee ◽  
Hans C. Dreyer ◽  
Shaheen Dhanani ◽  
Erin L. Glynn ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mammalian Target Of Rapamycin ◽  
Skeletal Muscle Protein ◽  
Capillary Recruitment ◽  
Isotope Tracers ◽  
Skeletal Muscle Protein Synthesis ◽  
Mtorc1 Signaling

Abstract Objective: Our objective was to determine whether endothelial-dependent vasodilation is an essential mechanism by which insulin stimulates human skeletal muscle protein synthesis and anabolism. Subjects: Subjects were healthy young adults (n = 14) aged 31 ± 2 yr. Design: Subjects were studied at baseline and during local leg infusion of insulin alone (control, n = 7) or insulin plus the nitric oxide synthase inhibitor NG-monomethyl-l-arginine (L-NMMA, n = 7) to prevent insulin-induced vasodilation. Methods: We measured skeletal muscle protein metabolism with stable isotope tracers, blood flow with indocyanine green, capillary recruitment with contrast enhanced ultrasound, glucose metabolism with stable isotope tracers, and phosphorylation of proteins associated with insulin (Akt) and amino acid-induced mammalian target of rapamycin(mTOR) complex 1 (mTORC1) signaling (mTOR, S6 kinase 1, and eukaryotic initiation factor 4Ebinding protein 1) with Western blot analysis. Results: No basal differences between groups were detected. During insulin infusion, blood flow and capillary recruitment increased in the control (P < 0.05) group only; Akt phosphorylation and glucose uptake increased in both groups (P < 0.05), with no group differences; and mTORC1 signaling increased more in control (P < 0.05) than in l-NMMA. Phenylalanine net balance increased (P < 0.05) in both groups, but with opposite mechanisms: increased protein synthesis (basal, 0.051 ± 0.006%/h; insulin, 0.077 ± 0.008%/h; P < 0.05) with no change in proteolysis in control and decreased proteolysis (P < 0.05) with no change in synthesis (basal, 0.061 ± 0.004%/h; insulin, 0.050 ± 0.006%/h; P value not significant) in l-NMMA. Conclusions: Endothelial-dependent vasodilation and the consequent increase in nutritive flow and mTORC1 signaling, rather than Akt signaling, are fundamental mechanisms by which insulin stimulates muscle protein synthesis in humans. Additionally, these data underscore that insulin modulates skeletal muscle proteolysis according to its effects on nutritive flow.

scholarly journals Activation of mTORC1 signaling and protein synthesis in human muscle following blood flow restriction exercise is inhibited by rapamycin

2014 ◽  
Vol 306 (10) ◽  
pp. E1198-E1204 ◽  
Author(s):  
David M. Gundermann ◽  
Dillon K. Walker ◽  
Paul T. Reidy ◽  
Michael S. Borack ◽  
Jared M. Dickinson ◽  
...  
Keyword(s):  
Blood Flow ◽  
Protein Synthesis ◽  
Time Course ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Vastus Lateralis ◽  
Human Muscle ◽  
Leg Extension ◽  
Or Groups ◽  
Mtorc1 Signaling

Restriction of blood flow to a contracting muscle during low-intensity resistance exercise (BFR exercise) stimulates mTORC1 signaling and protein synthesis in human muscle within 3 h postexercise. However, there is a lack of mechanistic data to provide a direct link between mTORC1 activation and protein synthesis in human skeletal muscle following BFR exercise. Therefore, the primary purpose of this study was to determine whether mTORC1 signaling is necessary for stimulating muscle protein synthesis after BFR exercise. A secondary aim was to describe the 24-h time course response in muscle protein synthesis and breakdown following BFR exercise. Sixteen healthy young men were randomized to one of two groups. Both the control (CON) and rapamycin (RAP) groups completed BFR exercise; however, RAP was administered 16 mg of the mTOR inhibitor rapamycin 1 h prior to BFR exercise. BFR exercise consisted of four sets of leg extension exercise at 20% of 1 RM. Muscle biopsies were collected from the vastus lateralis before exercise and at 3, 6, and 24 h after BFR exercise. Mixed-muscle protein fractional synthetic rate increased by 42% at 3 h postexercise and 69% at 24 h postexercise in CON, whereas this increase was inhibited in the RAP group. Phosphorylation of mTOR (Ser2448) and S6K1 (Thr389) was also increased in CON but inhibited in RAP. Mixed-muscle protein breakdown was not significantly different across time or groups. We conclude that activation of mTORC1 signaling and protein synthesis in human muscle following BFR exercise is inhibited in the presence of rapamycin.

scholarly journals Relationship between exercise volume and muscle protein synthesis in a rat model of resistance exercise

2017 ◽  
Vol 123 (4) ◽  
pp. 710-716 ◽  
Author(s):  
Riki Ogasawara ◽  
Yuki Arihara ◽  
Junya Takegaki ◽  
Koichi Nakazato ◽  
Naokata Ishii
Keyword(s):  
Protein Synthesis ◽  
Resistance Exercise ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mammalian Target Of Rapamycin ◽  
High Volume ◽  
Threshold Effect ◽  
Sprague Dawley ◽  
Downstream Target ◽  
The Relationship

Resistance exercise (RE) volume is recognized as an important factor that stimulates muscle protein synthesis (MPS) and is considered, at least in part, to be involved in the mammalian target of rapamycin complex 1 (mTORC1)-associated signaling. However, the effects of relatively high-volume RE on mTORC1 and MPS remain unclear. In the present study, we used an animal model of RE to investigate the relationship between RE volume and MPS. Male Sprague-Dawley rats were subjected to RE, and muscle samples were obtained 6 h after performing 1, 3, 5, 10, or 20 sets of RE. Although 1 set of RE did not increase MPS [measured by the surface sensing of translation (SUnSET) method], multiple sets (3, 5, 10, and 20 sets) significantly increased MPS. However, the increase in MPS reached a plateau after 3 or 5 sets of RE, and no further increase in MPS was observed with additional RE sets. In contrast to the MPS response, we observed that p70S6K phosphorylation at Thr389, a marker of mTORC1 activity, and Ser240/244 phosphorylation of rpS6, a downstream target of p70S6K, gradually increased with higher RE volume. The above results suggest that the relationship between RE volume and MPS was not linear. Thus the increase in MPS with increasing RE volume saturates before p70S6K phosphorylation, suggesting a threshold effect for the relationship between p70S6K activation and MPS. NEW & NOTEWORTHY The aim of this study was to investigate the relationship between resistance exercise (RE) volume and muscle protein synthesis. We found that the relationship between RE volume and p70S6K phosphorylation was almost linear, but the increase in muscle protein synthesis began to plateau after approximately five sets of RE.

scholarly journals Whey Protein Hydrolysate Increases Amino Acid Uptake, mTORC1 Signaling, and Protein Synthesis in Skeletal Muscle of Healthy Young Men in a Randomized Crossover Trial

2019 ◽  
Vol 149 (7) ◽  
pp. 1149-1158 ◽  
Author(s):  
Tatiana Moro ◽  
Camille R Brightwell ◽  
Brenda Velarde ◽  
Christopher S Fry ◽  
Kyosuke Nakayama ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Whey Protein ◽  
Crossover Trial ◽  
Muscle Protein ◽  
Protein Hydrolysate ◽  
Muscle Protein Synthesis ◽  
Young Men ◽  
Protein Sources ◽  
Mtorc1 Signaling ◽  
Whey Protein Hydrolysate

ABSTRACT Background Muscle protein synthesis (MPS) can be stimulated by ingestion of protein sources, such as whey, casein, or soy. Protein supplementation can enhance muscle protein synthesis after exercise and may preserve skeletal muscle mass and function in aging adults. Therefore, identifying protein sources with higher anabolic potency is of high significance. Objective The aim of this study was to determine the anabolic potency and efficacy of a novel whey protein hydrolysate mixture (WPH) on mechanistic target of rapamycin complex 1 (mTORC1) signaling and skeletal MPS in healthy young subjects. Methods Ten young men (aged 28.7 ± 3.6 y, 25.2 ± 2.9 kg/m2 body mass index [BMI]) were recruited into a double-blind two-way crossover trial. Subjects were randomized to receive either 0.08 g/kg of body weight (BW) of WPH or an intact whey protein (WHEY) mixture during stable isotope infusion experiments. Fractional synthetic rate, leucine and phenylalanine kinetics, and markers of amino acid sensing were assessed as primary outcomes before and 1–3 h after protein ingestion using a repeated measures mixed model. Results Blood leucine concentration, delivery of leucine to muscle, transport of leucine from blood into muscle and intracellular muscle leucine concentration significantly increased to a similar extent 1 h after ingestion of both mixtures (P < 0.05). Phosphorylation of S6K1 (i.e. a marker of mTORC1 activation) increased equally by ∼20% 1-h postingestion (P < 0.05). Ingestion of WPH and WHEY increased mixed MPS similarly in both groups by ∼43% (P < 0.05); however, phenylalanine utilization for synthesis increased in both treatments 1-h postingestion but remained elevated 3-h postingestion only in the WPH group (P < 0.05). Conclusions We conclude that a small dose of WPH effectively increases leucine transport into muscle, activating mTORC1 and stimulating MPS in young men. WPH anabolic potency and efficacy for promoting overall muscle protein anabolism is similar to WHEY, an intact protein source. This trial was registered at clinicaltrials.gov as NCT03313830.

scholarly journals The Paradoxical Effect of PARP Inhibitor BGP-15 on Irinotecan-Induced Cachexia and Skeletal Muscle Dysfunction

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3810
Author(s):  
Dean G. Campelj ◽  
Cara A. Timpani ◽  
Aaron C. Petersen ◽  
Alan Hayes ◽  
Craig A. Goodman ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Adjuvant Therapy ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Parp Inhibitor ◽  
Force Production ◽  
Musculotendinous Junction ◽  
Skeletal Myopathy ◽  
Mtorc1 Signaling

Chemotherapy-induced muscle wasting and dysfunction is a contributing factor to cachexia alongside cancer and increases the risk of morbidity and mortality. Here, we investigate the effects of the chemotherapeutic agent irinotecan (IRI) on skeletal muscle mass and function and whether BGP-15 (a poly-(ADP-ribose) polymerase-1 (PARP-1) inhibitor and heat shock protein co-inducer) adjuvant therapy could protect against IRI-induced skeletal myopathy. Healthy 6-week-old male Balb/C mice (n = 24; 8/group) were treated with six intraperitoneal injections of either vehicle, IRI (30 mg/kg) or BGP-15 adjuvant therapy (IRI+BGP; 15 mg/kg) over two weeks. IRI reduced lean and tibialis anterior mass, which were attenuated by IRI+BGP treatment. Remarkably, IRI reduced muscle protein synthesis, while IRI+BGP reduced protein synthesis further. These changes occurred in the absence of a change in crude markers of mammalian/mechanistic target of rapamycin (mTOR) Complex 1 (mTORC1) signaling and protein degradation. Interestingly, the cytoskeletal protein dystrophin was reduced in both IRI- and IRI+BGP-treated mice, while IRI+BGP treatment also decreased β-dystroglycan, suggesting significant remodeling of the cytoskeleton. IRI reduced absolute force production of the soleus and extensor digitorum longus (EDL) muscles, while IRI+BGP rescued absolute force production of the soleus and strongly trended to rescue force output of the EDL (p = 0.06), which was associated with improvements in mass. During the fatiguing stimulation, IRI+BGP-treated EDL muscles were somewhat susceptible to rupture at the musculotendinous junction, likely due to BGP-15’s capacity to maintain the rate of force development within a weakened environment characterized by significant structural remodeling. Our paradoxical data highlight that BGP-15 has some therapeutic advantage by attenuating IRI-induced skeletal myopathy; however, its effects on the remodeling of the cytoskeleton and extracellular matrix, which appear to make fast-twitch muscles more prone to tearing during contraction, could suggest the induction of muscular dystrophy and, thus, require further characterization.

scholarly journals Reactive hyperemia is not responsible for stimulating muscle protein synthesis following blood flow restriction exercise

2012 ◽  
Vol 112 (9) ◽  
pp. 1520-1528 ◽  
Author(s):  
David M. Gundermann ◽  
Christopher S. Fry ◽  
Jared M. Dickinson ◽  
Dillon K. Walker ◽  
Kyle L. Timmerman ◽  
...  
Keyword(s):  
Blood Flow ◽  
Protein Synthesis ◽  
Resistance Exercise ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Reactive Hyperemia ◽  
Blood Flow Restriction ◽  
Flow Restriction ◽  
Low Intensity ◽  
Mtorc1 Signaling

Blood flow restriction (BFR) to contracting skeletal muscle during low-intensity resistance exercise training increases muscle strength and size in humans. However, the mechanism(s) underlying these effects are largely unknown. We have previously shown that mammalian target of rapamycin complex 1 (mTORC1) signaling and muscle protein synthesis (MPS) are stimulated following an acute bout of BFR exercise. The purpose of this study was to test the hypothesis that reactive hyperemia is the mechanism responsible for stimulating mTORC1 signaling and MPS following BFR exercise. Six young men (24 ± 2 yr) were used in a randomized crossover study consisting of two exercise trials: low-intensity resistance exercise with BFR (BFR trial) and low-intensity resistance exercise with sodium nitroprusside (SNP), a pharmacological vasodilator infusion into the femoral artery immediately after exercise to simulate the reactive hyperemia response after BFR exercise (SNP trial). Postexercise mixed-muscle fractional synthetic rate from the vastus lateralis increased by 49% in the BFR trial ( P < 0.05) with no change in the SNP trial ( P > 0.05). BFR exercise increased the phosphorylation of mTOR, S6 kinase 1, ribosomal protein S6, ERK1/2, and Mnk1-interacting kinase 1 ( P < 0.05) with no changes in mTORC1 signaling in the SNP trial ( P > 0.05). We conclude that reactive hyperemia is not a primary mechanism for BFR exercise-induced mTORC1 signaling and MPS. Further research is necessary to elucidate the cellular mechanism(s) responsible for the increase in mTOR signaling, MPS, and hypertrophy following acute and chronic BFR exercise.

scholarly journals Insulin Stimulates Human Skeletal Muscle Protein Synthesis via an Indirect Mechanism Involving Endothelial-Dependent Vasodilation and Mammalian Target of Rapamycin Complex 1 Signaling

2010 ◽  
Vol 95 (8) ◽  
pp. 3848-3857 ◽  
Author(s):  
Kyle L. Timmerman ◽  
Jessica L. Lee ◽  
Hans C. Dreyer ◽  
Shaheen Dhanani ◽  
Erin L. Glynn ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mammalian Target Of Rapamycin ◽  
Skeletal Muscle Protein ◽  
Capillary Recruitment ◽  
Isotope Tracers ◽  
Skeletal Muscle Protein Synthesis ◽  
Mtorc1 Signaling

Objective: Our objective was to determine whether endothelial-dependent vasodilation is an essential mechanism by which insulin stimulates human skeletal muscle protein synthesis and anabolism. Subjects: Subjects were healthy young adults (n = 14) aged 31 ± 2 yr. Design: Subjects were studied at baseline and during local leg infusion of insulin alone (control, n = 7) or insulin plus the nitric oxide synthase inhibitor NG-monomethyl-l-arginine (l-NMMA, n = 7) to prevent insulin-induced vasodilation. Methods: We measured skeletal muscle protein metabolism with stable isotope tracers, blood flow with indocyanine green, capillary recruitment with contrast enhanced ultrasound, glucose metabolism with stable isotope tracers, and phosphorylation of proteins associated with insulin (Akt) and amino acid-induced mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling (mTOR, S6 kinase 1, and eukaryotic initiation factor 4E-binding protein 1) with Western blot analysis. Results: No basal differences between groups were detected. During insulin infusion, blood flow and capillary recruitment increased in the control (P &lt; 0.05) group only; Akt phosphorylation and glucose uptake increased in both groups (P &lt; 0.05), with no group differences; and mTORC1 signaling increased more in control (P &lt; 0.05) than in l-NMMA. Phenylalanine net balance increased (P &lt; 0.05) in both groups, but with opposite mechanisms: increased protein synthesis (basal, 0.051 ± 0.006 %/h; insulin, 0.077 ± 0.008 %/h; P &lt; 0.05) with no change in proteolysis in control and decreased proteolysis (P &lt; 0.05) with no change in synthesis (basal, 0.061 ± 0.004 %/h; insulin, 0.050 ± 0.006 %/h; P value not significant) in l-NMMA. Conclusions: Endothelial-dependent vasodilation and the consequent increase in nutritive flow and mTORC1 signaling, rather than Akt signaling, are fundamental mechanisms by which insulin stimulates muscle protein synthesis in humans. Additionally, these data underscore that insulin modulates skeletal muscle proteolysis according to its effects on nutritive flow.

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