Exercise increases phosphorylation of the putative mTORC2 activity readout NDRG1 in human skeletal muscle

2021 ◽  
Author(s):  
Jonas Roland Knudsen ◽  
Kaspar W Persson ◽  
Jaroslawna Meister ◽  
Christian Strini Carl ◽  
Steffen H Raun ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Human Skeletal Muscle ◽  
Ex Vivo ◽  
Vastus Lateralis ◽  
Published Data ◽  
Vastus Lateralis Muscle ◽  
Mouse Muscle ◽  
Exercise Induced ◽  
Stimulation Of

In mice, exercise is suggested to activate the mechanistic target of rapamycin complex 2 (mTORC2) in skeletal muscle, and mTORC2 is required for normal muscle glucose uptake during exercise. Whether this translates to human skeletal muscle and what signaling pathways facilitate the exercise-induced mTORC2 activation is unknown but important to determine given the important role of mTORC2 in metabolism. We herein tested the hypothesis that exercise increases mTORC2 activity in human skeletal muscle and investigated if β2-adrenergic receptor (AR) activation mediates exercise-induced mTORC2 activation. We examined several mTORC2 activity readouts (p-NDRG1 Thr346, p-Akt Ser473, p-mTOR S2481, and p-Akt Thr450) in human skeletal muscle biopsies after uphill walking or cycling exercise. In mouse muscles, we assessed mTORC2 activity readouts following acute activation of muscle β2-adrenergic or Gs signaling and during in vivo and ex vivo muscle contractions. Exercise increased phosphorylation of NDRG1 Thr346 in human soleus, gastrocnemius, and vastus lateralis muscle, without changing p-Akt Ser473, p-Akt Thr450, and p-mTOR Ser2481. In mouse muscle, stimulation of β2-adrenergic or Gs signaling and ex vivo contractions failed to increase p-NDRG1 Thr346, while in vivo contractions were sufficient to induce p-NDRG1 Thr346. In conclusion, the mTORC2 activity readout p-NDRG1 Thr346 is a novel exercise-responsive signaling protein in human skeletal muscle. Notably, contraction-induced p-NDRG1 Thr346 appears to require a systemic factor. Unlike exercise, and in contrast to published data obtained in cultured muscles cells, stimulation of β2-adrenergic signaling is not sufficient to trigger NDRG1 phosphorylation in mature mouse skeletal muscle.

scholarly journals Angiogenesis-related ultrastructural changes to capillaries in human skeletal muscle in response to endurance exercise

2015 ◽  
Vol 119 (10) ◽  
pp. 1118-1126 ◽  
Author(s):  
Oliver Baum ◽  
Jennifer Gübeli ◽  
Sebastian Frese ◽  
Eleonora Torchetti ◽  
Corinna Malik ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cross Sections ◽  
Human Skeletal Muscle ◽  
Vastus Lateralis ◽  
Capillary Density ◽  
Volume Density ◽  
Ultrastructural Changes ◽  
Vastus Lateralis Muscle ◽  
Before And After ◽  
Exercise Induced

The ultrastructure of capillaries in skeletal muscle was morphometrically assessed in vastus lateralis muscle (VL) biopsies taken before and after exercise from 22 participants of two training studies. In study 1 (8 wk of ergometer training), light microscopy revealed capillary-fiber (C/F) ratio (+27%) and capillary density (+16%) to be higher ( P ≤ 0.05) in postexercise biopsies than in preexercise biopsies from all 10 participants. In study 2 (6 mo of moderate running), C/F ratio and capillary density were increased (+23% and +20%; respectively, P ≤ 0.05) in VL biopsies from 6 angiogenesis responders (AR) after training, whereas 6 nonangiogenesis responders (NR) showed nonsignificant changes in these structural indicators (−4%/−4%, respectively). Forty capillary profiles per participant were evaluated by point and intersection counting on cross sections after transmission electron microscopy. In study 1, volume density (Vv) and mean arithmetic thickness (T) of endothelial cells (ECs; +19%/+17%, respectively) and pericytes (PCs; +20%/+21%, respectively) were higher ( P ≤ 0.05), whereas Vv and T of the pericapillary basement membrane (BM) were −23%/−22% lower ( P ≤ 0.05), respectively, in posttraining biopsies. In study 2, exercise-related differences between AR and NR-groups were found for Vv and T of PCs (AR, +26%/+22%, respectively, both P ≤ 0.05; NR, +1%/−3%, respectively, both P > 0.05) and BM (AR, −14%/−13%, respectively, both P ≤ 0.05; NR, −9%/−11%, respectively, P = 0.07/0.10). Vv and T of ECs were higher (AR, +16%/+18%, respectively; NR, +6% /+6%, respectively; all P ≤ 0.05) in both groups. The PC coverage was higher (+13%, P ≤ 0.05) in VL biopsies of individuals in the AR group but nonsignificantly altered (+3%, P > 0.05) in those of the NR group after training. Our study suggests that intensified PC mobilization and BM thinning are related to exercise-induced angiogenesis in human skeletal muscle, whereas training per se induces EC-thickening.

scholarly journals Local NSAID infusion inhibits satellite cell proliferation in human skeletal muscle after eccentric exercise

2009 ◽  
Vol 107 (5) ◽  
pp. 1600-1611 ◽  
Author(s):  
U. R. Mikkelsen ◽  
H. Langberg ◽  
I. C. Helmark ◽  
D. Skovgaard ◽  
L. L. Andersen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cell ◽  
Eccentric Exercise ◽  
Satellite Cells ◽  
Human Skeletal Muscle ◽  
Vastus Lateralis ◽  
Cell Activity ◽  
Inflammatory Cells ◽  
Vastus Lateralis Muscle

Despite the widespread consumption of nonsteroidal anti-inflammatory drugs (NSAIDs), the influence of these drugs on muscle satellite cells is not fully understood. The aim of the present study was to investigate the effect of a local NSAID infusion on satellite cells after unaccustomed eccentric exercise in vivo in human skeletal muscle. Eight young healthy males performed 200 maximal eccentric contractions with each leg. An NSAID was infused via a microdialysis catheter into the vastus lateralis muscle of one leg (NSAID leg) before, during, and for 4.5 h after exercise, with the other leg working as a control (unblocked leg). Muscle biopsies were collected before and 8 days after exercise. Changes in satellite cells and inflammatory cell numbers were investigated by immunohistochemistry. Satellite cells were identified using antibodies against neural cell adhesion molecule and Pax7. The number of Pax7+cells per myofiber was increased by 96% on day 8 after exercise in the unblocked leg (0.14 ± 0.04, mean ± SE) compared with the prevalue (0.07 ± 0.02, P < 0.05), whereas the number of Pax7+cells was unchanged in the leg muscles exposed to the NSAID (0.07 ± 0.01). The number of inflammatory cells (CD68+or CD16+cells) was not significantly increased in either of the legs 8 days after exercise and was unaffected by the NSAID. The main finding in the present study was that the NSAID infusion for 7.5 h during the exercise day suppressed the exercise-induced increase in the number of satellite cells 8 days after exercise. These results suggest that NSAIDs negatively affect satellite cell activity after unaccustomed eccentric exercise.

Physical exercise increases autophagic signaling through ULK1 in human skeletal muscle

2015 ◽  
Vol 118 (8) ◽  
pp. 971-979 ◽  
Author(s):  
Andreas Buch Møller ◽  
Mikkel Holm Vendelbo ◽  
Britt Christensen ◽  
Berthil Forrest Clasen ◽  
Ann Mosegaard Bak ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Physical Exercise ◽  
Light Chain ◽  
Human Skeletal Muscle ◽  
Transgenic Animal ◽  
Dependent Manner ◽  
Healthy Humans ◽  
Transgenic Animal Models ◽  
Exercise Induced

Data from transgenic animal models suggest that exercise-induced autophagy is critical for adaptation to physical training, and that Unc-51 like kinase-1 (ULK1) serves as an important regulator of autophagy. Phosphorylation of ULK1 at Ser555 stimulates autophagy, whereas phosphorylation at Ser757 is inhibitory. To determine whether exercise regulates ULK1 phosphorylation in humans in vivo in a nutrient-dependent manner, we examined skeletal muscle biopsies from healthy humans after 1-h cycling exercise at 50% maximal O2 uptake on two occasions: 1) during a 36-h fast, and 2) during continuous glucose infusion at 0.2 kg/h. Physical exercise increased ULK1 phosphorylation at Ser555 and decreased lipidation of light chain 3B. ULK1 phosphorylation at Ser555 correlated positively with AMP-activated protein kinase-α Thr172 phosphorylation and negatively with light chain 3B lipidation. ULK1 phosphorylation at Ser757 was not affected by exercise. Fasting increased ULK1 and p62 protein expression, but did not affect exercise-induced ULK1 phosphorylation. These data demonstrate that autophagy signaling is activated in human skeletal muscle after 60 min of exercise, independently of nutritional status, and suggest that initiation of autophagy constitutes an important physiological response to exercise in humans.

A single bout of exercise activates matrix metalloproteinase in human skeletal muscle

2007 ◽  
Vol 102 (6) ◽  
pp. 2346-2351 ◽  
Author(s):  
E. Rullman ◽  
H. Rundqvist ◽  
D. Wågsäter ◽  
H. Fischer ◽  
P. Eriksson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Matrix Metalloproteinase ◽  
Vastus Lateralis ◽  
Tissue Expression ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Vastus Lateralis Muscle ◽  
Protein Levels ◽  
Single Bout ◽  
Exercise Induced ◽  
Muscle Biopsies

The aims of this study were 1) to characterize changes in matrix metalloproteinase (MMP), endostatin, and vascular endothelial growth factor (VEGF)-A expression in skeletal muscle in response to a single bout of exercise in humans; and 2) to determine if any exchange of endostatin and VEGF-A between circulation and the exercising leg is associated with a change in the tissue expression or plasma concentration of these factors. Ten healthy males performed 65 min of cycle exercise, and muscle biopsies were obtained from the vastus lateralis muscle at rest and immediately and 120 min after exercise. In the muscle biopsies, measurements of mRNA expression levels of MMP-2, MMP-9, MMP-14, and tissue inhibitor of metalloproteinase; VEGF and endostatin protein levels; and MMP activities were performed. Femoral arterial and venous concentrations of VEGF-A and endostatin were determined before, during, and 120 min after exercise. A single bout of exercise increased MMP-9 mRNA and activated MMP-9 protein in skeletal muscle. No measurable increase of endostatin was observed in the skeletal muscle or in plasma following exercise. A concurrent increase in skeletal muscle VEGF-A mRNA and protein levels was induced by exercise, with no signs of peripheral uptake from the circulation. However, a decrease in plasma VEGF-A concentration occurred following exercise. Thus 1) a single bout of exercise activated the MMP system without any resulting change in tissue endostatin protein levels, and 2) the increased VEGF-A protein levels are due to changes in the skeletal muscle tissue itself. Other mechanisms are responsible for the observed exercise-induced decrease in VEGF-A in plasma.

Phosphorylase a in human skeletal muscle during exercise and electrical stimulation

1978 ◽  
Vol 45 (6) ◽  
pp. 852-857 ◽  
Author(s):  
P. D. Gollnick ◽  
J. Karlsson ◽  
K. Piehl ◽  
B. Saltin
Keyword(s):  
Skeletal Muscle ◽  
Electrical Stimulation ◽  
Human Skeletal Muscle ◽  
Vastus Lateralis ◽  
Muscular Activity ◽  
Voluntary Exercise ◽  
Vastus Lateralis Muscle ◽  
Minor Importance ◽  
Muscle Lactate ◽  
Needle Technique

Experiments were conducted to examine the conversions of phosphorylase b to phosphorylase a in human skeletal muscle during bicycle exercise or isometric contractions. Muscle biopsies were obtained from the vastus lateralis with the needle technique at rest and either during or immediately after activity and frozen in liquid nitrogen within 2--4 s. Total phosphorylase and phosphorylase a activities were differentiated by measurement in the presence and absence of AMP, respectively. At rest 8.5% of the total phosphorylase activity existed in the a form. Little or no change in the percent of phosphorylase in the a form occurred during voluntary dynamic or static muscular activity that produced muscle lactate concentrations in excess of 18 mmol.kg-1 wet muscle. Electrical stimulation of the vastus lateralis muscle also failed to produce an increase in the percentage of phosphorylase a. These data suggest that during exercise the conversion of phosphorylase to the a form is of minor importance. An increased activity of phosphorylase b due to changes in muscle concentrations of ATP, AMP, and inorganic phosphate may regulate glycogenolysis during voluntary exercise in man.

scholarly journals Contractile activity-specific transcriptome response to acute endurance exercise and training in human skeletal muscle

2019 ◽  
Vol 316 (4) ◽  
pp. E605-E614 ◽  
Author(s):  
Daniil V. Popov ◽  
Pavel A. Makhnovskii ◽  
Elena I. Shagimardanova ◽  
Guzel R. Gazizova ◽  
Evgeny A. Lysenko ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factors ◽  
Human Skeletal Muscle ◽  
Acute Exercise ◽  
Contractile Activity ◽  
Vastus Lateralis ◽  
Aerobic Exercise Training ◽  
Vastus Lateralis Muscle ◽  
Transcriptome Response ◽  
The One

Reduction in daily activity leads to dramatic metabolic disorders, while regular aerobic exercise training is effective for preventing this problem. The purpose of this study was to identify genes that are directly related to contractile activity in human skeletal muscle, regardless of the level of fitness. Transcriptome changes after the one-legged knee extension exercise in exercised and contralateral nonexercised vastus lateralis muscle of seven men were evaluated by RNA-seq. Transcriptome change at baseline after 2 mo of aerobic training (5/wk, 1 h/day) was evaluated as well. Postexercise changes in the transcriptome of exercised muscle were associated with different factors, including circadian oscillations. To reveal transcriptome response specific for endurance-like contractile activity, differentially expressed genes between exercised and nonexercised muscle were evaluated at 1 and 4 h after the one-legged exercise. The contractile activity-specific transcriptome responses were associated only with an increase in gene expression and were regulated mainly by CREB/ATF/AP1-, MYC/MAX-, and E2F-related transcription factors. Endurance training-induced changes (an increase or decrease) in the transcriptome at baseline were more pronounced than transcriptome responses specific for acute contractile activity. Changes after training were associated with widely different biological processes than those after acute exercise and were regulated by different transcription factors (IRF- and STAT-related factors). In conclusion, adaptation to regular exercise is associated not only with a transient (over several hours) increase in expression of many contractile activity-specific genes, but also with a pronounced change (an increase or decrease) in expression of a large number of genes under baseline conditions.

Eccentric exercise markedly increases c-Jun NH2-terminal kinase activity in human skeletal muscle

1999 ◽  
Vol 87 (5) ◽  
pp. 1668-1673 ◽  
Author(s):  
Marni D. Boppart ◽  
Doron Aronson ◽  
Lindsay Gibson ◽  
Ronenn Roubenoff ◽  
Leslie W. Abad ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Eccentric Exercise ◽  
Intracellular Signaling ◽  
Human Skeletal Muscle ◽  
Vastus Lateralis ◽  
Fold Increase ◽  
Mitogen Activated Protein Kinase ◽  
Eccentric Contractions ◽  
Vastus Lateralis Muscle

Eccentric contractions require the lengthening of skeletal muscle during force production and result in acute and prolonged muscle injury. Because a variety of stressors, including physical exercise and injury, can result in the activation of the c-Jun NH2-terminal kinase (JNK) intracellular signaling cascade in skeletal muscle, we investigated the effects of eccentric exercise on the activation of this stress-activated protein kinase in human skeletal muscle. Twelve healthy subjects (7 men, 5 women) completed maximal concentric or eccentric knee extensions on a KinCom isokinetic dynamometer (10 sets, 10 repetitions). Percutaneous needle biopsies were obtained from the vastus lateralis muscle 24 h before exercise (basal), immediately postexercise, and 6 h postexercise. Whereas both forms of exercise increased JNK activity immediately postexercise, eccentric contractions resulted in a much higher activation (15.4 ± 4.5 vs. 3.5 ± 1.4-fold increase above basal, eccentric vs. concentric). By 6 h after exercise, JNK activity decreased back to baseline values. In contrast to the greater activation of JNK with eccentric exercise, the mitogen-activated protein kinase kinase 4, the immediate upstream regulator of JNK, was similarly activated by concentric and eccentric exercise. Because the activation of JNK promotes the phosphorylation of a variety of transcription factors, including c-Jun, the results from this study suggest that JNK may be involved in the molecular and cellular adaptations that occur in response to injury-producing exercise in human skeletal muscle.

Effect of exercise on insulin action in human skeletal muscle

1989 ◽  
Vol 66 (2) ◽  
pp. 876-885 ◽  
Author(s):  
E. A. Richter ◽  
K. J. Mikines ◽  
H. Galbo ◽  
B. Kiens
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Insulin Action ◽  
Human Skeletal Muscle ◽  
Vastus Lateralis ◽  
Femoral Vein ◽  
Glycogen Synthesis ◽  
Vastus Lateralis Muscle ◽  
Glycogen Concentration ◽  
Local Contraction

The effect of 1 h of dynamic one-legged exercise on insulin action in human muscle was studied in 6 healthy young men. Four hours after one-legged knee extensions, a three-step sequential euglycemic hyperinsulinemic clamp combined with arterial and bilateral femoral vein catheterization was performed. Increased insulin action on glucose uptake was found in the exercised compared with the rested thigh at mean plasma insulin concentrations of 23, 40, and 410 microU/ml. Furthermore, prior contractions directed glucose uptake toward glycogen synthesis and increased insulin effects on thigh O2 consumption and at some insulin concentrations on potassium exchange. In contrast, no change in insulin effects on limb exchange of free fatty acids, glycerol, alanine or tyrosine were found after exercise. Glycogen concentration in rested vastus lateralis muscle did not increase measurably during the clamp even though indirect estimates indicated net glycogen synthesis. In contrast, in exercised muscle estimated and biopsy-verified increases in muscle glycogen concentration agreed. Local contraction-induced increases in insulin sensitivity and responsiveness play an important role in postexercise recovery of human skeletal muscle.

Human skeletal muscle malonyl-CoA at rest and during prolonged submaximal exercise

1996 ◽  
Vol 270 (3) ◽  
pp. E541-E544 ◽  
Author(s):  
L. M. Odland ◽  
G. J. Heigenhauser ◽  
G. D. Lopaschuk ◽  
L. L. Spriet
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
High Performance ◽  
Human Skeletal Muscle ◽  
Vastus Lateralis ◽  
Submaximal Exercise ◽  
Acid Oxidation ◽  
Vastus Lateralis Muscle ◽  
Malonyl Coa

Previous literature has indicated that contraction-induced decreases in malonyl-CoA are instrumental in the regulation of fatty acid oxidation during prolonged submaximal exercise. This study was designed to measure malonyl-CoA in human vastus lateralis muscle at rest and during submaximal exercise. Eight males and one female cycled for 70 min (10 min at 40% and 60 min at 65% maximal O2 uptake). Needle biopsies were obtained at rest and at 10 min, 20 min, and 70 min of exercise. Malonyl-CoA content in preexercise biopsy samples determined by high-performance liquid chromatography (HPLC) was 1.53 +/- 0.18 micromol/kg dry mass (dm). Malonyl-CoA content did not change significantly during exercise (1.39 +/- 0.21 at 10 min, 1.46 +/- 0.14 at 20 min, and 1.22 +/- 0.15 micromol/kg dm at 70 min). In contrast, malonyl-CoA content determined by HPLC in perfused rat red gastrocnemius muscle decreased significantly during 20 min of stimulation at 0.7 Hz [3.44 +/- 0.54 to 1.64 +/- 0.23 nmol/g dm, (n=9)]. We conclude that human skeletal muscle malonyl-CoA content 1) is less than reported in rat skeletal muscle at rest, 2) does not decrease with prolonged submaximal exercise, and 3) is not predictive of increased fatty acid oxidation during exercise.

α7β1-Integrin regulates mechanotransduction and prevents skeletal muscle injury

2006 ◽  
Vol 290 (6) ◽  
pp. C1660-C1665 ◽  
Author(s):  
Marni D. Boppart ◽  
Dean J. Burkin ◽  
Stephen J. Kaufman
Keyword(s):  
Skeletal Muscle ◽  
Muscle Damage ◽  
Intracellular Signaling ◽  
Ex Vivo ◽  
Negative Regulator ◽  
Blue Dye ◽  
The Matrix ◽  
Mitogen Activated Protein ◽  
Exercise Induced

α7β1-Integrin links laminin in the extracellular matrix with the cell cytoskeleton and therein mediates transduction of mechanical forces into chemical signals. Muscle contraction and stretching ex vivo result in activation of intracellular signaling molecules that are integral to postexercise injury responses. Because α7β1-integrin stabilizes muscle and provides communication between the matrix and cytoskeleton, the role of this integrin in exercise-induced cell signaling and skeletal muscle damage was assessed in wild-type and transgenic mice overexpressing the α7BX2 chain. We report here that increasing α7β1-integrin inhibits phosphorylation of molecules associated with muscle damage, including the mitogen-activated protein kinases (JNK, p38, and ERK), following downhill running. Likewise, activation of molecules associated with hypertrophy (AKT, mTOR, and p70S6k) was diminished in mice overexpressing integrin. While exercise resulted in Evans blue dye-positive fibers, an index of muscle damage, increased integrin protected mice from injury. Moreover, exercise leads to an increase in α7β1 protein. These experiments provide the first evidence that α7β1-integrin is a negative regulator of mechanotransduction in vivo and provides resistance to exercise-induced muscle damage.

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