scholarly journals Alcohol impairs skeletal muscle protein synthesis and mTOR signaling in a time-dependent manner following electrically stimulated muscle contraction

2014 ◽  
Vol 117 (10) ◽  
pp. 1170-1179 ◽  
Author(s):  
Jennifer L. Steiner ◽  
Charles H. Lang
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Saline Control ◽  
Dependent Manner ◽  
Skeletal Muscle Protein

Alcohol (EtOH) decreases protein synthesis and mammalian target of rapamycin (mTOR)-mediated signaling and blunts the anabolic response to growth factors in skeletal muscle. The purpose of the current investigation was to determine whether acute EtOH intoxication antagonizes the contraction-induced increase in protein synthesis and mTOR signaling in skeletal muscle. Fasted male mice were injected intraperitoneally with 3 g/kg EtOH or saline (control), and the right hindlimb was electrically stimulated (10 sets of 6 contractions). The gastrocnemius muscle complex was collected 30 min, 4 h, or 12 h after stimulation. EtOH decreased in vivo basal protein synthesis (PS) in the nonstimulated muscle compared with time-matched Controls at 30 min, 4 h, and 12 h. In Control, but not EtOH, PS was decreased 15% after 30 min. In contrast, PS was increased in Control 4 h poststimulation but remained unchanged in EtOH. Last, stimulation increased PS 10% in Control and EtOH at 12 h, even though the absolute rate remained reduced by EtOH. The stimulation-induced increase in the phosphorylation of S6K1 Thr421/Ser424 (20–52%), S6K1 Thr389 (45–57%), and its substrate rpS6 Ser240/244 (37–72%) was blunted by EtOH at 30 min, 4 h, and 12 h. Phosphorylation of 4E-BP1 Ser65 was also attenuated by EtOH (61%) at 4 h. Conversely, phosphorylation of extracellular signal-regulated kinase Thr202/Tyr204 was increased by stimulation in Control and EtOH mice at 30 min but only in Control at 4 h. Our data indicate that acute EtOH intoxication suppresses muscle protein synthesis for at least 12 h and greatly impairs contraction-induced changes in synthesis and mTOR signaling.

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 Novel insights into the regulation of skeletal muscle protein synthesis as revealed by a new nonradioactive in vivo technique

2010 ◽  
Vol 25 (3) ◽  
pp. 1028-1039 ◽  
Author(s):  
Craig A. Goodman ◽  
Danielle M. Mabrey ◽  
John W. Frey ◽  
Man Hing Miu ◽  
Enrico K. Schmidt ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Skeletal Muscle Protein ◽  
Skeletal Muscle Protein Synthesis

Alcohol impairs leucine-mediated phosphorylation of 4E-BP1, S6K1, eIF4G, and mTOR in skeletal muscle

2003 ◽  
Vol 285 (6) ◽  
pp. E1205-E1215 ◽  
Author(s):  
Charles H. Lang ◽  
Robert A. Frost ◽  
Nobuko Deshpande ◽  
Vinayshree Kumar ◽  
Thomas C. Vary ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Translational Control ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Plasma Concentrations ◽  
Mammalian Target Of Rapamycin ◽  
Initiation Factor ◽  
Skeletal Muscle Protein ◽  
Corticosterone Concentration

Acute alcohol (EtOH) intoxication impairs skeletal muscle protein synthesis. Although this impairment is not associated with a decrease in the total plasma amino acid concentration, EtOH may blunt the anabolic response to amino acids. To examine this hypothesis, rats were administered EtOH or saline (Sal) and 2.5 h thereafter were orally administered either leucine (Leu) or Sal. The gastrocnemius was removed 20 min later to assess protein synthesis and signaling components important in translational control of protein synthesis. Oral Leu increased muscle protein synthesis by the same magnitude in Sal- and EtOH-treated rats. However, the increase in the latter group was insufficient to overcome the suppressive effect of EtOH, and the rate of synthesis remained lower than that observed in rats from the Sal-Sal group. Leu markedly increased phosphorylation of Thr residues 36, 47, and 70 on 4E-binding protein (BP)1 in muscle from rats not receiving EtOH, and this response was associated with a redistribution of eukaryotic initiation factor (eIF) 4E from the inactive eIF4E · 4E-BP1 to the active eIF4E · eIF4G complex. In EtOH-treated rats, the Leu-induced phosphorylation of 4E-BP1 and changes in eIF4E availability were partially abrogated. EtOH also prevented the Leu-induced increase in phosphorylation of eIF4G, the serine/threonine protein kinase S6K1, and the ribosomal protein S6. Moreover, EtOH attenuated the Leu-induced phosphorylation of the mammalian target of rapamycin (mTOR). The ability of EtOH to blunt the anabolic effects of Leu could not be attributed to differences in the plasma concentrations of insulin, insulin-like growth factor I, or Leu. Finally, although EtOH increased the plasma corticosterone concentration, inhibition of glucocorticoid action by RU-486 was unable to prevent EtOH-induced defects in the ability of Leu to stimulate 4E-BP1, S6K1, and mTOR phosphorylation. Hence, ethanol produces a leucine resistance in skeletal muscle, as evidenced by the impaired phosphorylation of 4E-BP1, eIF4G, S6K1, and mTOR, that is independent of elevations in endogenous glucocorticoids.

Phosphorylation of eukaryotic initiation factor eIF2Bε in skeletal muscle during sepsis

2002 ◽  
Vol 283 (5) ◽  
pp. E1032-E1039 ◽  
Author(s):  
Thomas C. Vary ◽  
Gina Deiter ◽  
Scot R. Kimball
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Glycogen Synthase ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Sterile Inflammation ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Skeletal Muscle Protein

We reported that the inhibition of protein synthesis in skeletal muscle during sepsis correlated with reduced eukaryotic initiation factor eIF2B activity. The present studies define changes in eIF2Bε phosphorylation in gastrocnemius of septic animals. eIF2B kinase activity was significantly elevated 175% by sepsis compared with sterile inflammation, whereas eIF2B phosphatase activity was unaffected. Phosphorylation of eIF2Bε-Ser535 was significantly augmented over 2-fold and 2.5-fold after 3 and 5 days and returned to control values after 10 days of sepsis. Phosphorylation of glycogen synthase kinase-3 (GSK-3), a potential upstream kinase responsible for the elevated phosphorylation of eIF2Bε, was significantly reduced over 36 and 41% after 3 and 5 days and returned to control values after 10 days of sepsis. The phosphorylation of PKB, a kinase thought to directly phosphorylate and inactivate GSK-3, was significantly reduced ∼50% on day 3, but not on days 5 or 10, postinfection compared with controls. Treatment of septic rats with TNF-binding protein prevented the sepsis-induced changes in eIF2Bε and GSK-3 phosphorylation, implicating TNF in mediating the effects of sepsis. Thus increased phosphorylation of eIF2Bε via activation of GSK-3 is an important mechanism to account for the inhibition of skeletal muscle protein synthesis during sepsis. Furthermore, the study presents the first demonstration of changes in eIF2Bε phosphorylation in vivo.

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 < 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.

Neuromuscular electrical stimulation increases muscle protein synthesis in elderly type 2 diabetic men

2012 ◽  
Vol 303 (5) ◽  
pp. E614-E623 ◽  
Author(s):  
Benjamin T. Wall ◽  
Marlou L. Dirks ◽  
Lex B. Verdijk ◽  
Tim Snijders ◽  
Dominique Hansen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Neuromuscular Electrical Stimulation ◽  
Skeletal Muscle Protein ◽  
Skeletal Muscle Protein Synthesis ◽  
Type 2 Diabetic

Physical activity is required to attenuate the loss of skeletal muscle mass with aging. Short periods of muscle disuse, due to sickness or hospitalization, reduce muscle protein synthesis rates, resulting in rapid muscle loss. The present study investigates the capacity of neuromuscular electrical stimulation (NMES) to increase in vivo skeletal muscle protein synthesis rates in older type 2 diabetes patients. Six elderly type 2 diabetic men (70 ± 2 yr) were subjected to 60 min of one-legged NMES. Continuous infusions with l-[ ring-13C6]phenylalanine were applied, with blood and muscle samples being collected regularly to assess muscle protein synthesis rates in both the stimulated (STIM) and nonstimulated control (CON) leg during 4 h of recovery after NMES. Furthermore, mRNA expression of key genes implicated in the regulation of muscle mass were measured over time in the STIM and CON leg. Muscle protein synthesis rates were greater in the STIM compared with the CON leg during recovery from NMES (0.057 ± 0.008 vs. 0.045 ± 0.008%/h, respectively, P < 0.01). Skeletal muscle myostatin mRNA expression in the STIM leg tended to increase immediately following NMES compared with the CON leg (1.63- vs. 1.00-fold, respectively, P = 0.07) but strongly declined after 2 and 4 h of recovery in the STIM leg only. In conclusion, this is the first study to show that NMES directly stimulates skeletal muscle protein synthesis rates in vivo in humans. NMES likely represents an effective interventional strategy to attenuate muscle loss in elderly individuals during bed rest and/or in other disuse states.

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