scholarly journals Effect of N-acetylcysteine infusion on exercise-induced modulation of insulin sensitivity and signaling pathways in human skeletal muscle

2015 ◽  
Vol 309 (4) ◽  
pp. E388-E397 ◽  
Author(s):  
Adam J. Trewin ◽  
Leonidas S. Lundell ◽  
Ben D. Perry ◽  
Kim Vikhe Patil ◽  
Alexander V. Chibalin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Repeated Measures ◽  
Insulin Action ◽  
Human Skeletal Muscle ◽  
Protein Signaling ◽  
Insulin Stimulation ◽  
Double Blind ◽  
Exercise Induced ◽  
Muscle Biopsies

—Reactive oxygen species (ROS) produced in skeletal muscle may play a role in potentiating the beneficial responses to exercise; however, the effects of exercise-induced ROS on insulin action and protein signaling in humans has not been fully elucidated. Seven healthy, recreationally active participants volunteered for this double-blind, randomized, repeated-measures crossover study. Exercise was undertaken with infusion of saline (CON) or the antioxidant N-acetylcysteine (NAC) to attenuate ROS. Participants performed two 1-h cycling exercise sessions 7–14 days apart, 55 min at 65% V̇o2peak plus 5 min at 85%V̇o2peak, followed 3 h later by a 2-h hyperinsulinemic euglycemic clamp (40 mIU·min−1·m2) to determine insulin sensitivity. Four muscle biopsies were taken on each trial day, at baseline before NAC infusion (BASE), after exercise (EX), after 3-h recovery (REC), and post-insulin clamp (PI). Exercise, ROS, and insulin action on protein phosphorylation were evaluated with immunoblotting. NAC tended to decrease postexercise markers of the ROS/protein carbonylation ratio by −13.5% ( P = 0.08) and increase the GSH/GSSG ratio twofold vs. CON ( P < 0.05). Insulin sensitivity was reduced (−5.9%, P < 0.05) by NAC compared with CON without decreased phosphorylation of Akt or AS160. Whereas p-mTOR was not significantly decreased by NAC after EX or REC, phosphorylation of the downstream protein synthesis target kinase p70S6K was blunted by 48% at PI with NAC compared with CON ( P < 0.05). We conclude that NAC infusion attenuated muscle ROS and postexercise insulin sensitivity independent of Akt signaling. ROS also played a role in normal p70S6K phosphorylation in response to insulin stimulation in human skeletal muscle.

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

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

Activation of skeletal muscle calpain-3 by eccentric exercise in humans does not result in its translocation to the nucleus or cytosol

2011 ◽  
Vol 111 (5) ◽  
pp. 1448-1458 ◽  
Author(s):  
Robyn M. Murphy ◽  
Kristian Vissing ◽  
Heidy Latchman ◽  
Cedric Lamboley ◽  
Michael J. McKenna ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Eccentric Exercise ◽  
Repeated Measures ◽  
Human Skeletal Muscle ◽  
Exercise Intervention ◽  
Calpain 3 ◽  
Functional Consequences ◽  
Exercise Induced ◽  
Post Hoc ◽  
Exercise In Humans

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.

Reduced carbohydrate availability enhances exercise-induced p53 signaling in human skeletal muscle: implications for mitochondrial biogenesis

2013 ◽  
Vol 304 (6) ◽  
pp. R450-R458 ◽  
Author(s):  
Jonathan D. Bartlett ◽  
Jari Louhelainen ◽  
Zafar Iqbal ◽  
Andrew J. Cochran ◽  
Martin J. Gibala ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Repeated Measures ◽  
Human Skeletal Muscle ◽  
Vastus Lateralis ◽  
Oxidative Capacity ◽  
Pyruvate Dehydrogenase Kinase ◽  
Repeated Measures Design ◽  
P53 Signaling ◽  
Exercise Induced

The mechanisms that regulate the enhanced skeletal muscle oxidative capacity observed when training with reduced carbohydrate (CHO) availability are currently unknown. The aim of the present study was to test the hypothesis that reduced CHO availability enhances p53 signaling and expression of genes associated with regulation of mitochondrial biogenesis and substrate utilization in human skeletal muscle. In a repeated-measures design, muscle biopsies (vastus lateralis) were obtained from eight active males before and after performing an acute bout of high-intensity interval running with either high (HIGH) or low CHO availability (LOW). Resting muscle glycogen (HIGH, 467 ± 19; LOW, 103 ± 9 mmol/kg dry wt) was greater in HIGH compared with LOW ( P < 0.05). Phosphorylation (P-) of ACCSer79 (HIGH, 1.4 ± 0.4; LOW, 2.9 ± 0.9) and p53Ser15 (HIGH, 0.9 ± 0.4; LOW, 2.6 ± 0.8) was higher in LOW immediately postexercise and 3 h postexercise, respectively ( P < 0.05). Before and 3 h postexercise, mRNA content of pyruvate dehydrogenase kinase 4, mitochondrial transcription factor A, cytochrome- c oxidase IV, and PGC-1α were greater in LOW compared with HIGH ( P < 0.05), whereas carnitine palmitoyltransferase-1 showed a trend toward significance ( P = 0.09). However, only PGC-1α expression was increased by exercise ( P < 0.05), where three-fold increases occurred independently of CHO availability. We conclude that the exercise-induced increase in p53 phosphorylation is enhanced in conditions of reduced CHO availability, which may be related to upstream signaling through AMPK. Given the emergence of p53 as a molecular regulator of mitochondrial biogenesis, such nutritional modulation of contraction-induced p53 activation has implications for both athletic and clinical populations.

scholarly journals Pathways in Skeletal Muscle: Protein Signaling and Insulin Sensitivity after Exercise Training and Weight Loss Interventions in Middle-Aged and Older Adults

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3490
Author(s):  
Alice S. Ryan ◽  
Guoyan Li ◽  
Shawna McMillin ◽  
Steven J. Prior ◽  
Jacob B. Blumenthal ◽  
...  
Keyword(s):  
Older Adults ◽  
Skeletal Muscle ◽  
Weight Loss ◽  
Insulin Sensitivity ◽  
Exercise Training ◽  
Insulin Receptor ◽  
Aerobic Exercise Training ◽  
Protein Signaling ◽  
Insulin Stimulation ◽  
Gsk 3Β

Aging and obesity contribute to insulin resistance with skeletal muscle being critically important for maintaining whole-body glucose homeostasis. Both exercise and weight loss are lifestyle interventions that can affect glucose metabolism. The purpose of this study was to examine the effects of a six-month trial of aerobic exercise training or weight loss on signaling pathways in skeletal muscle in the basal condition and during hyperinsulinemia during a glucose clamp in middle-aged and older adults. Overweight and obese men and women aged 50–70 years were randomly allocated and completed six months of either weight loss (WL) (n = 18) or 3x/week aerobic exercise training (AEX) (n = 17). WL resulted in 10% weight loss and AEX increased maximal oxygen consumption (VO2max) (both p < 0.001). Insulin sensitivity (hyperinsulinemic-euglycemic 80 mU·m−2·min−1 clamp) increased in WL and AEX (both p < 0.01). In vivo insulin stimulation increased phosphorylation/total protein ratio (P/T) of protein kinase B (Akt), glycogen synthase kinase 3 beta (GSK-β3), 70 kDa ribosomal protein S6 kinase (p70S6k), insulin receptor substrate 1 (IRS-1), and insulin receptor (IR) expression (all p < 0.05) but not P/T extracellular regulated kinase ½ (ERK1/2), c-jun N-terminal kinases (JNK), p38 mitogen-activated protein kinases (p38), or insulin-like growth factor 1 receptor (IGF-1R). There were differences between WL and AEX in the change in basal Akt P/T (p = 0.05), GSK-3β P/T ratio (p < 0.01), p70S6k (p < 0.001), ERK1/2 (p = 0.01) P/T ratio but not p38, JNK, IRS-1, and IGF-1R P/T ratios. There was a difference between WL and AEX in the insulin stimulation changes in GSK3 which increased more after WL than AEX (p < 0.05). In the total group, changes in M were associated with changes in basal total GSK-3β and basal total p70Sk as well as insulin stimulation of total p70Sk. Protein signaling in skeletal muscle provides insight as to mechanisms for improvements in insulin sensitivity in aging and obesity.

Bed rest reduces metabolic protein content and abolishes exercise-induced mRNA responses in human skeletal muscle

2011 ◽  
Vol 301 (4) ◽  
pp. E649-E658 ◽  
Author(s):  
Stine Ringholm ◽  
Rasmus S. Biensø ◽  
Kristian Kiilerich ◽  
Amelia Guadalupe-Grau ◽  
Niels Jacob Aachmann-Andersen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Content ◽  
Human Skeletal Muscle ◽  
Citrate Synthase ◽  
Bed Rest ◽  
Sirtuin 1 ◽  
Vastus Lateralis Muscle ◽  
Before And After ◽  
Exercise Induced ◽  
Muscle Biopsies

The aim was to test the hypothesis that 7 days of bed rest reduces mitochondrial number and expression and activity of oxidative proteins in human skeletal muscle but that exercise-induced intracellular signaling as well as mRNA and microRNA (miR) responses are maintained after bed rest. Twelve young, healthy male subjects completed 7 days of bed rest with vastus lateralis muscle biopsies taken before and after bed rest. In addition, muscle biopsies were obtained from six of the subjects prior to, immediately after, and 3 h after 45 min of one-legged knee extensor exercise performed before and after bed rest. Maximal oxygen uptake decreased by 4%, and exercise endurance decreased nonsignificantly, by 11%, by bed rest. Bed rest reduced skeletal muscle mitochondrial DNA/nuclear DNA content 15%, hexokinase II and sirtuin 1 protein content ∼45%, 3-hydroxyacyl-CoA dehydrogenase and citrate synthase activity ∼8%, and miR-1 and miR-133a content ∼10%. However, cytochrome c and vascular endothelial growth factor (VEGF) protein content as well as capillarization did not change significantly with bed rest. Acute exercise increased AMP-activated protein kinase phosphorylation, peroxisome proliferator activated receptor-γ coactivator-1α, and VEGF mRNA content in skeletal muscle before bed rest, but the responses were abolished after bed rest. The present findings indicate that only 7 days of physical inactivity reduces skeletal muscle metabolic capacity as well as abolishes exercise-induced adaptive gene responses, likely reflecting an interference with the ability of skeletal muscle to adapt to exercise.

Exercise-induced enhancement of insulin sensitivity is associated with accumulation of M2-polarized macrophages in mouse skeletal muscle

2013 ◽  
Vol 441 (1) ◽  
pp. 36-41 ◽  
Author(s):  
Shin-ichi Ikeda ◽  
Yoshifumi Tamura ◽  
Saori Kakehi ◽  
Kageumi Takeno ◽  
Minako Kawaguchi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Mouse Skeletal Muscle ◽  
Exercise Induced

Does impaired mitochondrial function affect insulin signaling and action in cultured human skeletal muscle cells?

2008 ◽  
Vol 294 (1) ◽  
pp. E97-E102 ◽  
Author(s):  
Audrey E. Brown ◽  
Matthias Elstner ◽  
Stephen J. Yeaman ◽  
Douglass M. Turnbull ◽  
Mark Walker
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Mitochondrial Respiration ◽  
Respiratory Function ◽  
Insulin Action ◽  
Human Skeletal Muscle ◽  
Human Skeletal Muscle Cells ◽  
Basal Glucose Uptake

Insulin-resistant type 2 diabetic patients have been reported to have impaired skeletal muscle mitochondrial respiratory function. A key question is whether decreased mitochondrial respiration contributes directly to the decreased insulin action. To address this, a model of impaired cellular respiratory function was established by incubating human skeletal muscle cell cultures with the mitochondrial inhibitor sodium azide and examining the effects on insulin action. Incubation of human skeletal muscle cells with 50 and 75 μM azide resulted in 48 ± 3% and 56 ± 1% decreases, respectively, in respiration compared with untreated cells mimicking the level of impairment seen in type 2 diabetes. Under conditions of decreased respiratory chain function, insulin-independent (basal) glucose uptake was significantly increased. Basal glucose uptake was 325 ± 39 pmol/min/mg (mean ± SE) in untreated cells. This increased to 669 ± 69 and 823 ± 83 pmol/min/mg in cells treated with 50 and 75 μM azide, respectively (vs. untreated, both P < 0.0001). Azide treatment was also accompanied by an increase in basal glycogen synthesis and phosphorylation of AMP-activated protein kinase. However, there was no decrease in glucose uptake following insulin exposure, and insulin-stimulated phosphorylation of Akt was normal under these conditions. GLUT1 mRNA expression remained unchanged, whereas GLUT4 mRNA expression increased following azide treatment. In conclusion, under conditions of impaired mitochondrial respiration there was no evidence of impaired insulin signaling or glucose uptake following insulin exposure in this model system.

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

2004 ◽  
Vol 287 (6) ◽  
pp. E1189-E1194 ◽  
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.

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.

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