Effect of Resistance Exercise with Blood Flow Restriction on Muscle Protein Synthesis and mTOR Signaling in Older Men

Low-intensity resistance exercise training combined with blood flow restriction (REFR) increases muscle size and strength as much as conventional resistance exercise with high loads. However, the cellular mechanism(s) underlying the hypertrophy and strength gains induced by REFR are unknown. We have recently shown that both the mammalian target of rapamycin (mTOR) signaling pathway and muscle protein synthesis (MPS) were stimulated after an acute bout of high-intensity resistance exercise in humans. Therefore, we hypothesized that an acute bout of REFR would enhance mTOR signaling and stimulate MPS. We measured MPS and phosphorylation status of mTOR-associated signaling proteins in six young male subjects. Subjects were studied once during blood flow restriction (REFR, bilateral leg extension exercise at 20% of 1 repetition maximum while a pressure cuff was placed on the proximal end of both thighs and inflated at 200 mmHg) and a second time using the same exercise protocol but without the pressure cuff [control (Ctrl)]. MPS in the vastus lateralis muscle was measured by using stable isotope techniques, and the phosphorylation status of signaling proteins was determined by immunoblotting. Blood lactate, cortisol, and growth hormone were higher following REFR compared with Ctrl ( P < 0.05). Ribosomal S6 kinase 1 (S6K1) phosphorylation, a downstream target of mTOR, increased concurrently with a decreased eukaryotic translation elongation factor 2 (eEF2) phosphorylation and a 46% increase in MPS following REFR ( P < 0.05). MPS and S6K1 phosphorylation were unchanged in the Ctrl group postexercise. We conclude that the activation of the mTOR signaling pathway appears to be an important cellular mechanism that may help explain the enhanced muscle protein synthesis during REFR.

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Blood Flow Restriction during Low-Intensity Resistance Exercise Increases Muscle Protein Synthesis through the mTOR Signaling Pathway

Medicine & Science in Sports & Exercise ◽

10.1249/01.mss.0000273025.20580.1b ◽

2007 ◽

Vol 39 (Supplement) ◽

pp. S36

Author(s):

Satoshi Fujita ◽

Takashi Abe ◽

Micah J. Drummond ◽

Jerson G. Cadenas ◽

Hans C. Dreyer ◽

...

Keyword(s):

Blood Flow ◽

Protein Synthesis ◽

Resistance Exercise ◽

Signaling Pathway ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Blood Flow Restriction ◽

Mtor Signaling Pathway ◽

Flow Restriction ◽

Low Intensity

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

Journal of Applied Physiology ◽

10.1152/japplphysiol.01267.2011 ◽

2012 ◽

Vol 112 (9) ◽

pp. 1520-1528 ◽

Cited By ~ 55

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.

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Blood flow restriction exercise stimulates mTORC1 signaling and muscle protein synthesis in older men

Journal of Applied Physiology ◽

10.1152/japplphysiol.01266.2009 ◽

2010 ◽

Vol 108 (5) ◽

pp. 1199-1209 ◽

Cited By ~ 164

Author(s):

Christopher S. Fry ◽

Erin L. Glynn ◽

Micah J. Drummond ◽

Kyle L. Timmerman ◽

Satoshi Fujita ◽

...

Keyword(s):

Blood Flow ◽

Protein Synthesis ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Older Men ◽

Signaling Proteins ◽

Flow Restriction ◽

Low Intensity ◽

Pressure Cuff ◽

Mtorc1 Signaling

The loss of skeletal muscle mass during aging, sarcopenia, increases the risk for falls and dependence. Resistance exercise (RE) is an effective rehabilitation technique that can improve muscle mass and strength; however, older individuals are resistant to the stimulation of muscle protein synthesis (MPS) with traditional high-intensity RE. Recently, a novel rehabilitation exercise method, low-intensity RE, combined with blood flow restriction (BFR), has been shown to stimulate mammalian target of rapamycin complex 1 (mTORC1) signaling and MPS in young men. We hypothesized that low-intensity RE with BFR would be able to activate mTORC1 signaling and stimulate MPS in older men. We measured MPS and mTORC1-associated signaling proteins in seven older men (age 70 ± 2 yr) before and after exercise. Subjects were studied identically on two occasions: during BFR exercise [bilateral leg extension exercise at 20% of 1-repetition maximum (1-RM) with pressure cuff placed proximally on both thighs and inflated at 200 mmHg] and during exercise without the pressure cuff (Ctrl). MPS and phosphorylation of signaling proteins were determined on successive muscle biopsies by stable isotopic techniques and immunoblotting, respectively. MPS increased 56% from baseline after BFR exercise ( P < 0.05), while no change was observed in the Ctrl group ( P > 0.05). Downstream of mTORC1, ribosomal S6 kinase 1 (S6K1) phosphorylation and ribosomal protein S6 (rpS6) phosphorylation increased only in the BFR group after exercise ( P < 0.05). We conclude that low-intensity RE in combination with BFR enhances mTORC1 signaling and MPS in older men. BFR exercise is a novel intervention that may enhance muscle rehabilitation to counteract sarcopenia.

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Exercise May Promote Skeletal Muscle Hypertrophy via Enhancing Leucine-Sensing: Preliminary Evidence

Frontiers in Physiology ◽

10.3389/fphys.2021.741038 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yan Zhao ◽

Jason Cholewa ◽

Huayu Shang ◽

Yueqin Yang ◽

Xiaomin Ding ◽

...

Keyword(s):

Protein Synthesis ◽

Resistance Exercise ◽

Aerobic Exercise ◽

Protein Concentration ◽

Muscle Hypertrophy ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Muscle Fibers ◽

Mtor Signaling ◽

Treadmill Running

Several studies have indicated a positive effect of exercise (especially resistance exercise) on the mTOR signaling that control muscle protein synthesis and muscle remodeling. However, the relationship between exercise, mTOR activation and leucine-sensing requires further clarification. Two month old Sprague-Dawley rats were subjected to aerobic exercise (treadmill running at 20 m/min, 6° incline for 60 min) and resistance exercise (incremental ladder climbing) for 4 weeks. The gastrocnemius muscles were removed for determination of muscle fibers diameter, cross-sectional area (CSA), protein concentration and proteins involved in muscle leucine-sensing and protein synthesis. The results show that 4 weeks of resistance exercise increased the diameter and CSA of gastrocnemius muscle fibers, protein concentration, the phosphorylation of mTOR (Ser2448), 4E-BP1(Thr37/46), p70S6K (Thr389), and the expression of LeuRS, while aerobic exercise just led to a significant increase in protein concentration and the phosphorylation of 4E-BP1(Thr37/46). Moreover, no difference was found for Sestrin2 expression between groups. The current study shows resistance exercise, but not aerobic exercise, may increase muscle protein synthesis and protein deposition, and induces muscle hypertrophy through LeuRS/mTOR signaling pathway. However, further studies are still warranted to clarify the exact effects of vary intensities and durations of aerobic exercise training.

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Muscle Protein Synthesis is Enhanced Post-Resistance Exercise by Nutrient Stimulation of the mTOR Signaling Pathway

Medicine & Science in Sports & Exercise ◽

10.1249/01.mss.0000273232.79203.ce ◽

2007 ◽

Vol 39 (Supplement) ◽

pp. S82-S83

Author(s):

Hans C. Dreyer ◽

Micah J. Drummond ◽

Satoshi Fujita ◽

Erin L. Glynn ◽

Bart Pennings ◽

...

Keyword(s):

Protein Synthesis ◽

Resistance Exercise ◽

Signaling Pathway ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Stimulation Of

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Influence of nutrient ingestion on amino acid transporters and protein synthesis in human skeletal muscle after sprint exercise

Journal of Applied Physiology ◽

10.1152/japplphysiol.00244.2017 ◽

2017 ◽

Vol 123 (6) ◽

pp. 1501-1515 ◽

Cited By ~ 3

Author(s):

Håkan C. Rundqvist ◽

Mona Esbjörnsson ◽

Olav Rooyackers ◽

Ted Österlund ◽

Marcus Moberg ◽

...

Keyword(s):

Protein Synthesis ◽

Amino Acid ◽

Resistance Exercise ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Amino Acid Transporter ◽

Mtor Signaling ◽

Sprint Exercise ◽

Phosphorylated Akt ◽

Acid Transporter

Nutrient ingestion is known to increase the exercise-induced stimulation of muscle protein synthesis following resistance exercise. Less is known about the effect of nutrients on muscle protein synthesis following sprint exercise. At two occasions separated by 1 mo, 12 healthy subjects performed three 30-s sprints with 20-min rest between bouts. In randomized order, they consumed a drink with essential amino acids and maltodextrin (nutrient) or flavored water (placebo). Muscle biopsies were obtained 80 and 200 min after the last sprint, and blood samples were taken repeatedly during the experiment. Fractional synthetic rate (FSR) was measured by continuous infusion of l-[2H5]phenylalanine up to 200 min postexercise. The mRNA expression and protein expression of SNAT2 were both 1.4-fold higher ( P < 0.05) after nutrient intake compared with placebo at 200 min postexercise. Phosphorylated Akt, mammalian target of rapamycin (mTOR), and p70S6k were 1.7- to 3.6-fold higher ( P < 0.01) 80 min after the last sprint with nutrient ingestion as compared with placebo. In addition, FSR was higher ( P < 0.05) with nutrients when plasma phenylalanine (FSRplasma) was used as a precursor but not when intracellular phenylalanine (FSRmuscle) was used. Significant correlations were also found between FSRplasma on the one hand and plasma leucine and serum insulin on the other hand in the nutrient condition. The results show that nutrient ingestion induces the expression of the amino acid transporter SNAT2 stimulates Akt/mTOR signaling and most likely the rate of muscle protein synthesis following sprint exercise. NEW & NOTEWORTHY There is limited knowledge regarding the effect of nutrients on muscle protein synthesis following sprint as compared with resistance exercise. The results demonstrate that nutrient ingestion during repeated 30-s bouts of sprint exercise induces expression of the amino acid transporter SNAT2 and stimulates Akt/mTOR signaling and most likely the rate of muscle protein synthesis. Future studies to explore the chronic effects of nutritional ingestion during sprint exercise sessions on muscle mass accretion are warranted.

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Enriching a protein drink with leucine augments muscle protein synthesis after resistance exercise in young and older men

Clinical Nutrition ◽

10.1016/j.clnu.2016.04.025 ◽

2017 ◽

Vol 36 (3) ◽

pp. 888-895 ◽

Cited By ~ 29

Author(s):

Philip J. Atherton ◽

Vinod Kumar ◽

Anna L. Selby ◽

Debbie Rankin ◽

Wulf Hildebrandt ◽

...

Keyword(s):

Protein Synthesis ◽

Resistance Exercise ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Older Men

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The impact of delivery profile of essential amino acids upon skeletal muscle protein synthesis in older men: clinical efficacy of pulse vs. bolus supply

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00112.2015 ◽

2015 ◽

Vol 309 (5) ◽

pp. E450-E457 ◽

Cited By ~ 26

Author(s):

W. Kyle Mitchell ◽

Bethan E. Phillips ◽

John P. Williams ◽

Debbie Rankin ◽

Jonathan N. Lund ◽

...

Keyword(s):

Skeletal Muscle ◽

Amino Acids ◽

Blood Flow ◽

Protein Synthesis ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Older Men ◽

Essential Amino Acids ◽

Low Amplitude ◽

The Impact

Essential amino acids (EAA) are responsible for skeletal muscle anabolic effects after nutrient intake. The pattern of appearance of EAA in blood, e.g., after intake of “slow” or “fast” protein sources or in response to grazing vs. bolus feeding patterns, may impact anabolism. However, the influence of this on muscle anabolism is poorly understood, particularly in older individuals. We determined the effects of divergent feeding profiles of EAA on blood flow, anabolic signaling, and muscle protein synthesis (MPS) in older men. Sixteen men (∼70 yr) consumed EAA either as a single dose (bolus, 15 g; n = 8) or as small repeated fractions (pulse, 4 × 3.75 g every 45 min; n = 8) during 13C6 phenylalanine infusion. Repeated blood samples and muscle biopsies permitted measurement of fasting and postprandial plasma EAA, insulin, anabolic signaling, and MPS. Muscle blood flow was assessed by contrast-enhanced ultrasound (Sonovue). Bolus achieved rapid insulinemia (12.7 μiU/ml 25-min postfeed), essential aminoacidemia (∼3,000 μM, 45–65 min postfeed), and mTORC1 activity; pulse achieved attenuated insulin responses, gradual low-amplitude aminoacidemia (∼1,800 μM 80–195 min after feeding), and undetectable mTORC1 signaling. Despite this, equivalent anabolic responses were observed: fasting FSRs of 0.051 and 0.047%/h (bolus and pulse, respectively) increased to 0.084 and 0.073%/h, respectively. Moreover, pulse led to sustainment of MPS beyond 180 min, when bolus MPS had returned to basal rates. We detected no benefit of rapid aminoacidemia in this older population despite enhanced anabolic signaling and greater overall EAA exposure. Rather, apparent delayed onset of the “muscle-full” effect permitted identical MPS following low-amplitude-sustained EAA exposure.

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