Activation of NF-kB in Pericytes of Human Skeletal Muscle Following Eccentric Exercise-Induced Damage

The skeletal muscle-specific calpain-3 protease is likely involved in muscle repair, although the mechanism is not known. Physiological activation of calpain-3 occurs 24 h following eccentric exercise in humans. Functional consequences of calpain-3 activation are not known; however, calpain-3 has been suggested to be involved in nuclear signaling via NF-κB. To test this and help identify how/where calpain-3 acts, we investigated whether calpain-3 autolysis (hence, activation) following eccentric exercise results in translocation from its normal myofibrillar location to the nucleus or the cytosol. In resting human skeletal muscle, the majority (87%) of calpain-3 was present in myofibrillar fractions, with only a small proportion (<10%) in an autolyzed state. Enriched nuclear fractions contained ∼8% of the total calpain-3, which was present in a predominantly (>80%) autolyzed state. Using freshly dissected human muscle fibers to identify freely diffusible proteins, we showed that only ∼5% of the total calpain-3 pool was cytosolic. At 3 and 24 h following eccentric step exercise, there was an ∼70% increase in autolysis in whole muscle samples ( n = 11, P < 0.05, by 1-way ANOVA with repeated measures and Newman-Keuls post hoc analysis). This exercise-induced autolysis was attributed to myofibrillar-bound calpain-3, since neither the amount of calpain-3 nor the proportion autolyzed was significantly changed in enriched nuclear or cytosolic fractions following the exercise intervention. We present a model for calpain-3 localization at rest and following activation in human skeletal muscle and suggest that the functional importance of calpain-3 remains predominantly tightly associated with its localization within the myofibrillar compartment.

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Endurance training reduces the contraction-induced interleukin-6 mRNA expression in human skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00206.2004 ◽

2004 ◽

Vol 287 (6) ◽

pp. E1189-E1194 ◽

Cited By ~ 84

Author(s):

Christian P. Fischer ◽

Peter Plomgaard ◽

Anne K. Hansen ◽

Henriette Pilegaard ◽

Bengt Saltin ◽

...

Keyword(s):

Skeletal Muscle ◽

Mrna Expression ◽

Muscle Glycogen ◽

Human Skeletal Muscle ◽

Acute Exercise ◽

Glycogen Content ◽

Knee Extensor ◽

Exercise Induced ◽

Response To Exercise ◽

Resting Muscle

Contracting skeletal muscle expresses large amounts of IL-6. Because 1) IL-6 mRNA expression in contracting skeletal muscle is enhanced by low muscle glycogen content, and 2) IL-6 increases lipolysis and oxidation of fatty acids, we hypothesized that regular exercise training, associated with increased levels of resting muscle glycogen and enhanced capacity to oxidize fatty acids, would lead to a less-pronounced increase of skeletal muscle IL-6 mRNA in response to acute exercise. Thus, before and after 10 wk of knee extensor endurance training, skeletal muscle IL-6 mRNA expression was determined in young healthy men ( n = 7) in response to 3 h of dynamic knee extensor exercise, using the same relative workload. Maximal power output, time to exhaustion during submaximal exercise, resting muscle glycogen content, and citrate synthase and 3-hydroxyacyl-CoA dehydrogenase enzyme activity were all significantly enhanced by training. IL-6 mRNA expression in resting skeletal muscle did not change in response to training. However, although absolute workload during acute exercise was 44% higher ( P < 0.05) after the training period, skeletal muscle IL-6 mRNA content increased 76-fold ( P < 0.05) in response to exercise before the training period, but only 8-fold ( P < 0.05, relative to rest and pretraining) in response to exercise after training. Furthermore, the exercise-induced increase of plasma IL-6 ( P < 0.05, pre- and posttraining) was not higher after training despite higher absolute work intensity. In conclusion, the magnitude of the exercise-induced IL-6 mRNA expression in contracting human skeletal muscle was markedly reduced by 10 wk of training.

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Physical exercise increases autophagic signaling through ULK1 in human skeletal muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.01116.2014 ◽

2015 ◽

Vol 118 (8) ◽

pp. 971-979 ◽

Cited By ~ 58

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.

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Skeletal muscle adaptations to exercise are not influenced by metformin treatment in humans: secondary analyses of two randomised, clinical trials.

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2021-0194 ◽

2021 ◽

Author(s):

Nanna Skytt Pilmark ◽

Laura Oberholzer ◽

Jens Frey Halling ◽

Jonas M. Kristensen ◽

Christina Pedersen Bønding ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Exercise Training ◽

Human Skeletal Muscle ◽

Acute Exercise ◽

Metformin Treatment ◽

Ampk Activation ◽

Double Blind ◽

Parallel Group ◽

Exercise Induced

Metformin and exercise both improve glycemic control, but in vitro studies have indicated that an interaction between metformin and exercise occurs in skeletal muscle, suggesting a blunting effect of metformin on exercise training adaptations. Two studies (a double-blind, parallel-group, randomized clinical trial conducted in 29 glucose-intolerant individuals and a double-blind, cross-over trial conducted in 15 healthy lean males) were included in this paper. In both studies, the effect of acute exercise +/- metformin treatment on different skeletal muscle variables, previously suggested to be involved in a pharmaco-physiological interaction between metformin and exercise, was assessed. Furthermore, in the parallel-group trial, the effect of 12 weeks of exercise training was assessed. Skeletal muscle biopsies were obtained before and after acute exercise and 12 weeks of exercise training, and mitochondrial respiration, oxidative stress and AMPK activation was determined. Metformin did not significantly affect the effects of acute exercise or exercise training on mitochondrial respiration, oxidative stress or AMPK activation, indicating that the response to acute exercise and exercise training adaptations in skeletal muscle is not affected by metformin treatment. Further studies are needed to investigate whether an interaction between metformin and exercise is present in other tissues, e.g. the gut. Trial registration: ClinicalTrials.gov (NCT03316690 and NCT02951260). Novelty bullets • Metformin does not affect exercise-induced alterations in mitochondrial respiratory capacity in human skeletal muscle • Metformin does not affect exercise-induced alterations in systemic levels of oxidative stress nor emission of reactive oxygen species from human skeletal muscle • Metformin does not affect exercise-induced AMPK activation in human skeletal muscle

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Eccentric exercise‐induced morphological changes in the membrane systems involved in excitation—contraction coupling in rat skeletal muscle

The Journal of Physiology ◽

10.1111/j.1469-7793.2001.0571a.x ◽

2001 ◽

Vol 533 (2) ◽

pp. 571-583 ◽

Cited By ~ 125

Author(s):

Hiroaki Takekura ◽

Nahoko Fujinami ◽

Tomie Nishizawa ◽

Hitomi Ogasawara ◽

Norikatsu Kasuga

Keyword(s):

Skeletal Muscle ◽

Eccentric Exercise ◽

Morphological Changes ◽

Membrane Systems ◽

Rat Skeletal Muscle ◽

Excitation Contraction Coupling ◽

Contraction Coupling ◽

Exercise Induced

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Repeatability of exercise-induced changes in mRNA expression and technical considerations for qPCR analysis in human skeletal muscle

Experimental Physiology ◽

10.1113/ep087401 ◽

2019 ◽

Vol 104 (3) ◽

pp. 407-420 ◽

Cited By ~ 15

Author(s):

Hashim Islam ◽

Brittany A. Edgett ◽

Jacob T. Bonafiglia ◽

Talya Shulman ◽

Andrew Ma ◽

...

Keyword(s):

Skeletal Muscle ◽

Mrna Expression ◽

Human Skeletal Muscle ◽

Qpcr Analysis ◽

Exercise Induced ◽

Induced Changes ◽

Technical Considerations

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

Journal of Applied Physiology ◽

10.1152/jappl.1999.87.5.1668 ◽

1999 ◽

Vol 87 (5) ◽

pp. 1668-1673 ◽

Cited By ~ 62

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.

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Oral glucose ingestion attenuates exercise-induced activation of 5′-AMP-activated protein kinase in human skeletal muscle

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2006.02.057 ◽

2006 ◽

Vol 342 (3) ◽

pp. 949-955 ◽

Cited By ~ 47

Author(s):

Thorbjorn C.A. Akerstrom ◽

Jesper B. Birk ◽

Ditte K. Klein ◽

Christian Erikstrup ◽

Peter Plomgaard ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Human Skeletal Muscle ◽

Oral Glucose ◽

Glucose Ingestion ◽

Exercise Induced ◽

Amp Activated Protein Kinase

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Effect of green tea extract supplementation on glycogen replenishment in exercised human skeletal muscle

British Journal Of Nutrition ◽

10.1017/s0007114517001374 ◽

2017 ◽

Vol 117 (10) ◽

pp. 1343-1350 ◽

Cited By ~ 4

Author(s):

Tsen-Wei Tsai ◽

Chia-Chen Chang ◽

Su-Fen Liao ◽

Yi-Hung Liao ◽

Chien-Wen Hou ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Content ◽

Green Tea ◽

Muscle Glycogen ◽

Human Skeletal Muscle ◽

Recovery Period ◽

Glycogen Resynthesis ◽

Postexercise Recovery ◽

Exercise Induced ◽

Tea Extract

AbstractThe purpose of this study was to investigate the effects of 8-week green tea extract (GTE) supplementation on promoting postexercise muscle glycogen resynthesis and systemic energy substrate utilisation in young college students. A total of eight healthy male participants (age: 22·0 (se 1·0) years, BMI: 24·2 (se 0·7) kg/m2, VO2max: 43·2 (se 2·4) ml/kg per min) participated in this study. GTE (500 mg/d for 8 weeks) was compared with placebo in participants in a double-blind/placebo-controlled and crossover study design with an 8-week washout period. Thereafter, all participants performed a 60-min cycling exercise (75 % VO2max) and consumed a carbohydrate-enriched meal immediately after exercise. Vastus lateralis muscle samples were collected immediately (0 h) and 3 h after exercise, and blood and gaseous samples were collected during the 3-h postexercise recovery period. An 8-week oral GTE supplementation had no effects on further promoting muscle glycogen resynthesis in exercised human skeletal muscle, but the exercise-induced muscle GLUT type 4 (GLUT4) protein content was greater in the GTE supplementation trial (P<0·05). We observed that, during the postexercise recovery period, GTE supplementation elicited an increase in energy reliance on fat oxidation compared with the placebo trial (P<0·05), although there were no differences in blood glucose and insulin responses between the two trials. In summary, 8-week oral GTE supplementation increases postexercise systemic fat oxidation and exercise-induced muscle GLUT4 protein content in response to an acute bout of endurance exercise. However, GTE supplementation has no further benefit on promoting muscle glycogen resynthesis during the postexercise period.

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