scholarly journals Protein arginine methyltransferase biology in humans during acute and chronic skeletal muscle plasticity

2019 ◽  
Vol 127 (3) ◽  
pp. 867-880 ◽  
Author(s):  
Tiffany L. vanLieshout ◽  
Jacob T. Bonafiglia ◽  
Brendon J. Gurd ◽  
Vladimir Ljubicic
Keyword(s):  
Skeletal Muscle ◽  
Human Skeletal Muscle ◽  
Acute Exercise ◽  
Human Muscle ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Muscle Plasticity ◽  
Arginine Residues ◽  
Expression And Activity

Protein arginine methyltransferases (PRMTs) are a family of enzymes that catalyze the methylation of arginine residues on target proteins. While dysregulation of PRMTs has been documented in a number of the most prevalent diseases, our understanding of PRMT biology in human skeletal muscle is limited. This study served to address this knowledge gap by exploring PRMT expression and function in human skeletal muscle in vivo and characterizing PRMT biology in response to acute and chronic stimuli for muscle plasticity. Fourteen untrained, healthy men performed one session of sprint interval exercise (SIE) before completing four bouts of SIE per week for 6 wk as part of a sprint interval training (SIT) program. Throughout this time course, multiple muscle biopsies were collected. We found that at basal, resting conditions PRMT1, PRMT4, PRMT5, and PRMT7 were the most abundantly expressed PRMT mRNAs in human quadriceps muscle. Additionally, the broad subcellular distribution pattern of PRMTs suggests methyltransferase activity throughout human myofibers. A spectrum of PRMT-specific inductions, and decrements, in expression and activity were observed in response to acute and chronic cues for muscle plasticity. In conclusion, our findings demonstrate that PRMTs are present and active in human skeletal muscle in vivo and that there are distinct, enzyme-specific responses and adaptations in PRMT biology to acute and chronic stimuli for muscle plasticity. This work advances our understanding of this critical family of enzymes in humans. NEW & NOTEWORTHY This is the first report of protein arginine methyltransferase (PRMT) biology in human skeletal muscle in vivo. We observed that PRMT1, -4, -5, and -7 were the most abundant PRMT mRNAs in human muscle and that PRMT proteins exhibited a broad subcellular localization that included myonuclear, cytosolic, and sarcolemmal compartments. Acute exercise and chronic training evoked PRMT-specific alterations in expression and activity. This study reveals a hitherto unknown complexity to PRMT biology in human muscle.

scholarly journals Protein arginine methyltransferase expression, localization, and activity during disuse-induced skeletal muscle plasticity

2018 ◽  
Vol 314 (2) ◽  
pp. C177-C190 ◽  
Author(s):  
Derek W. Stouth ◽  
Alexander Manta ◽  
Vladimir Ljubicic
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Muscle Plasticity ◽  
Arginine Residues ◽  
Expression And Activity

Protein arginine methyltransferase 1 (PRMT1), PRMT4, and PRMT5 catalyze the methylation of arginine residues on target proteins. Previous work suggests that these enzymes regulate skeletal muscle plasticity. However, the function of PRMTs during disuse-induced muscle remodeling is unknown. The purpose of our study was to determine whether denervation-induced muscle disuse alters PRMT expression and activity in skeletal muscle, as well as to contextualize PRMT biology within the early disuse-evoked events that precede atrophy, which remain largely undefined. Mice were subjected to 6, 12, 24, 72, or 168 h of unilateral hindlimb denervation. Muscle mass decreased by ~30% after 72 or 168 h of neurogenic disuse, depending on muscle fiber type composition. The expression, localization, and activities of PRMT1, PRMT4, and PRMT5 were modified, exhibiting changes in gene expression and activity that were PRMT-specific. Rapid alterations in canonical muscle atrophy signaling such as forkhead box protein O1, muscle RING-finger protein-1, as well as peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) content, AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase, were observed before measurable decrements in muscle mass. Denervation-induced modifications in AMPK-PRMT1 and PGC-1α-PRMT1 binding revealed a novel, putative PRMT1-AMPK-PGC-1α signaling axis in skeletal muscle. Here, PGC-1α-PRMT1 binding was elevated after 6 h of disuse, whereas AMPK-PRMT1 interactions were reduced following 168 h of denervation. Our data suggest that PRMT biology is integral to the mechanisms that precede and initiate skeletal muscle atrophy during conditions of neurogenic disuse. This study furthers our understanding of the role of PRMTs in governing skeletal muscle plasticity.

Localization and function of ATP-sensitive potassium channels in human skeletal muscle

2003 ◽  
Vol 284 (2) ◽  
pp. R558-R563 ◽  
Author(s):  
Jens Jung Nielsen ◽  
Michael Kristensen ◽  
Ylva Hellsten ◽  
Jens Bangsbo ◽  
Carsten Juel
Keyword(s):  
Skeletal Muscle ◽  
Muscle Activity ◽  
Human Skeletal Muscle ◽  
Knee Extensor ◽  
Human Muscle ◽  
Functional Importance ◽  
Gradient Technique ◽  
And Function

The present study investigated the localization of ATP-sensitive K+ (KATP) channels in human skeletal muscle and the functional importance of these channels for human muscle K+ distribution at rest and during muscle activity. Membrane fractionation based on the giant vesicle technique or the sucrose-gradient technique in combination with Western blotting demonstrated that the KATP channels are mainly located in the sarcolemma. This localization was confirmed by immunohistochemical measurements. With the microdialysis technique, it was demonstrated that local application of the KATP channel inhibitor glibenclamide reduced ( P < 0.05) interstitial K+ at rest from ∼4.5 to 4.0 mM, whereas the concentration in the control leg remained constant. Glibenclamide had no effect on the interstitial K+ accumulation during knee-extensor exercise at a power output of 60 W. In contrast to in vitro conditions, the present study demonstrated that under in vivo conditions the KATP channels are active at rest and contribute to the accumulation of interstitial K+.

Exercise-induced Protein Arginine Methyltransferase Expression in Skeletal Muscle

2018 ◽  
Vol 50 (3) ◽  
pp. 447-457 ◽  
Author(s):  
TIFFANY L. VANLIESHOUT ◽  
DEREK W. STOUTH ◽  
TANIA TAJIK ◽  
VLADIMIR LJUBICIC
Keyword(s):  
Skeletal Muscle ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Exercise Induced

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.

Exercise training increases branched-chain oxoacid dehydrogenase kinase content in human skeletal muscle

2007 ◽  
Vol 293 (3) ◽  
pp. R1335-R1341 ◽  
Author(s):  
Krista R. Howarth ◽  
Kirsten A. Burgomaster ◽  
Stuart M. Phillips ◽  
Martin J. Gibala
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Protein Content ◽  
Human Skeletal Muscle ◽  
Acute Exercise ◽  
Citrate Synthase ◽  
Muscle Protein ◽  
Moderate Intensity ◽  
Main Effect ◽  
Branched Chain

The branched-chain oxoacid dehydrogenase complex (BCOAD) is rate determining for the oxidation of branched-chain amino acids (BCAAs) in skeletal muscle. Exercise training blunts the acute exercise-induced activation of BCOAD (BCOADa) in human skeletal muscle (McKenzie S, Phillips SM, Carter SL, Lowther S, Gibala MJ, Tarnopolsky MA. Am J Physiol Endocrinol Metab 278: E580–E587, 2000); however, the mechanism is unknown. We hypothesized that training would increase the muscle protein content of BCOAD kinase, the enzyme responsible for inactivation of BCOAD by phosphorylation. Twenty subjects [23 ± 1 yr; peak oxygen uptake (V̇o2peak) = 41 ± 2 ml·kg−1·min−1] performed 6 wk of either high-intensity interval or continuous moderate-intensity training on a cycle ergometer ( n = 10/group). Before and after training, subjects performed 60 min of cycling at 65% of pretraining V̇o2peak, and needle biopsy samples (vastus lateralis) were obtained before and immediately after exercise. The effect of training was demonstrated by an increased V̇o2peak, increased citrate synthase maximal activity, and reduced muscle glycogenolysis during exercise, with no difference between groups (main effects, P < 0.05). BCOADa was lower after training (main effect, P < 0.05), and this was associated with a ∼30% increase in BCOAD kinase protein content (main effect, P < 0.05). We conclude that the increased protein content of BCOAD kinase may be involved in the mechanism for reduced BCOADa after exercise training in human skeletal muscle. These data also highlight differences in models used to study the regulation of skeletal muscle BCAA metabolism, since exercise training was previously reported to increase BCOADa during exercise and decrease BCOAD kinase content in rats (Fujii H, Shimomura Y, Murakami T, Nakai N, Sato T, Suzuki M, Harris RA. Biochem Mol Biol Int 44: 1211–1216, 1998).

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

scholarly journals Satellite cells in human skeletal muscle plasticity

2015 ◽  
Vol 6 ◽  
Author(s):  
Tim Snijders ◽  
Joshua P. Nederveen ◽  
Bryon R. McKay ◽  
Sophie Joanisse ◽  
Lex B. Verdijk ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Human Skeletal Muscle ◽  
Muscle Plasticity

scholarly journals FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis

2021 ◽  
Vol 118 (37) ◽  
pp. e2021013118 ◽  
Author(s):  
Sebastian Mathes ◽  
Alexandra Fahrner ◽  
Umesh Ghoshdastider ◽  
Hannes A. Rüdiger ◽  
Michael Leunig ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transcriptional Activation ◽  
Human Skeletal Muscle ◽  
Muscle Growth ◽  
Muscle Cells ◽  
Adeno Associated Virus ◽  
Adult Skeletal Muscle

Aged skeletal muscle is markedly affected by fatty muscle infiltration, and strategies to reduce the occurrence of intramuscular adipocytes are urgently needed. Here, we show that fibroblast growth factor-2 (FGF-2) not only stimulates muscle growth but also promotes intramuscular adipogenesis. Using multiple screening assays upstream and downstream of microRNA (miR)-29a signaling, we located the secreted protein and adipogenic inhibitor SPARC to an FGF-2 signaling pathway that is conserved between skeletal muscle cells from mice and humans and that is activated in skeletal muscle of aged mice and humans. FGF-2 induces the miR-29a/SPARC axis through transcriptional activation of FRA-1, which binds and activates an evolutionary conserved AP-1 site element proximal in the miR-29a promoter. Genetic deletions in muscle cells and adeno-associated virus–mediated overexpression of FGF-2 or SPARC in mouse skeletal muscle revealed that this axis regulates differentiation of fibro/adipogenic progenitors in vitro and intramuscular adipose tissue (IMAT) formation in vivo. Skeletal muscle from human donors aged >75 y versus <55 y showed activation of FGF-2–dependent signaling and increased IMAT. Thus, our data highlights a disparate role of FGF-2 in adult skeletal muscle and reveals a pathway to combat fat accumulation in aged human skeletal muscle.

scholarly journals Microdialysis of skeletal muscle at rest

1999 ◽  
Vol 58 (4) ◽  
pp. 919-923 ◽  
Author(s):  
Jan Henriksson
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Human Skeletal Muscle ◽  
Human Metabolism ◽  
High Expectations ◽  
Perfusate Flow ◽  
Muscle Research ◽  
Interstitial Glucose

Techniques in human skeletal muscle research are by necessity predominantly 'descriptive'.Microdialysis has raised high expectations that it could meet the demand for a method that allows 'mechanistic' investigations to be performed in human skeletal muscle. In the present review, some views are given on how well the initial expectations on the use of the microdialysis technique in skeletal muscle have been fulfilled, and the areas in which additional work is needed in order to validate microdialysis as an important metabolic technique in this tissue. The microdialysis catheter has been equated to an artificial blood vessel, which is introduced into the tissue. By means of this 'vessel' the concentrations of compounds in the interstitial space can be monitored. The concentration of substances in the collected samples is dependent on the rate of perfusate flow. When perfusate flow is slow enough to allow complete equilibration between interstitial and perfusate fluids, the concentration in the perfusate is maximal and identical to the interstitial concentration. Microdialysis data may be influenced by changes in blood flow, especially in instances where the tissue diffusivity limits the recovery in vivo, i.e. when recovery in vitro is 100 %, whereas the recovery in vivo is less than 100 %. Microdialysis data indicate that a significant arterial-interstitial glucose concentration gradient exists in skeletal muscle but not in adipose tissue at rest. While the concentrations of glucose and lactate in the dialysate from skeletal muscle are close to the expected values, the glycerol values obtained for muscle are still puzzling. Ethanol added to the perfusate will be cleared by the tissue at a rate that is determined by the nutritive blood flow (the microdialysis ethanol technique). It is concluded that microdialysis of skeletal muscle has become an important technique for mechanistic studies in human metabolism and nutrition.

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