Biology subjects

Bangsbo, J.

Publications and source records attributed to Bangsbo, J..

9 recordsLinked to original sources

bioRxiv2024

Muscle fiber proteomics reveals sex- and fiber type-specific adaptations to resistance training

Skeletal muscle hypertrophy is a hallmark of resistance training that positively impacts health and longevity. However, despite physiological differences between sexes and fiber types, the underlying proteome changes with resistance training have not been studied in a sex- and fiber type-specific manner. Herein, we show sex differences in the fiber type-specific proteome, predominantly in type II fibers. Following 8 weeks of resistance training, substantial remodeling of the human skeletal muscle proteome occurred in a sex- and fiber type-specific manner. Notably, type II fibers exhibited much greater adaptations across both sexes, whereas the main sex-difference was a greater remodeling of intermediate filaments in females. In addition, baseline abundance of proteins involved in translation was highly correlated with fiber hypertrophy, and differed between sexes and fiber types. Thus, translational capacity may partially explain differences in resistance training-induced hypertrophy. Our findings demonstrate key aspects of sex- and fiber type differences in muscle physiology and their contributions to resistance training-induced adaptions.

physiology↗

bioRxiv2023

Insulin and Exercise-induced Phosphoproteomics of Human Skeletal Muscle Identify REPS1 as a New Regulator of Muscle Glucose Uptake

Skeletal muscle regulates glucose uptake in response to insulin and exercise which is critical for maintaining metabolic health. We conducted a comprehensive phosphoproteomic analysis of skeletal muscle from healthy people in response to an acute bout of exercise or insulin stimulation by a hyperinsulinemic euglycemic clamp. Our analysis revealed 233 phosphosites regulated by both exercise and insulin of which most phosphosites were regulated in opposite directions. However, 71 phosphosites on 55 proteins displayed regulation in the same direction, indicating a potential convergence of signaling pathways. We identified the vesicle-associated protein, REPS1, to be phosphorylated at Ser709 in response to both insulin and exercise. REPS1 protein level and Ser709 phosphorylation were closely related to insulin-stimulated glucose uptake in skeletal muscle and required for maximal insulin-stimulated glucose uptake. Furthermore, we observed that insulin triggered phosphorylation of REPS1 Ser709 via P90S6 kinase (RSK) and is impaired in mice and humans with insulin resistance. Collectively, REPS1 is a convergence point for insulin and exercise signaling and a promising therapeutic target in insulin resistance.

biochemistry↗

bioRxiv2023

Reducing the mitochondrial oxidative burden alleviates lipid-induced insulin resistance in human skeletal muscle

Pre-clinical models suggest a causative nexus between mitochondrial oxidative stress and insulin resistance. However, the translational and pathophysiological significance of this mechanism in humans remains unclear. Herein, we employed an invasive in vivo mechanistic approach in humans to manipulate mitochondrial redox state while assessing insulin action. To this end, we combined intravenous infusion of a lipid overload with intake of a mitochondria-targeted antioxidant (mtAO) in conjunction with insulin clamp studies. During lipid overload, insulin-stimulated muscle glucose uptake, as determined by the femoral arteriovenous balance technique, was increased by mtAO. At the muscle molecular level, mtAO did not affect canonical insulin signaling but augmented insulin-stimulated GLUT4 translocation while decreasing the mitochondrial oxidative burden under lipid oversupply. Ex vivo studies revealed that mtAO ameliorated features of mitochondrial bioenergetics, including diminished mitochondrial H2O2 emission, in muscle fibers exposed to high intracellular lipid levels. These findings provide translational and mechanistic evidence implicating mitochondrial oxidants in the development of lipid-induced muscle insulin resistance in humans. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/535538v2_ufig1.gif" ALT="Figure 1"> View larger version (86K): org.highwire.dtl.DTLVardef@157d44eorg.highwire.dtl.DTLVardef@13358dborg.highwire.dtl.DTLVardef@e958eorg.highwire.dtl.DTLVardef@17cbc6f_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2021

Beta2-adrenoceptor agonist salbutamol increases leg glucose uptake and metabolic rate but not muscle glycogen resynthesis in recovery from resistance exercise of the quadriceps in lean young men

ContentBeta2-agonists evoke potent acute increases in peripheral glucose uptake and energy expenditure at rest. Exercise has been shown to blunt these effects. Whether this attenuation is extended into recovery from exercise is unknown. ObjectiveTo examine the effect of beta2-agonists on leg glucose uptake and leg metabolic rate in recovery from exercise. DesignIn a randomized, placebo-controlled, cross-over study using arteriovenous balance technique and analysis of thigh muscle biopsies we investigated the effect of 24mg oral salbutamol (a selective beta2-agonist) on leg glucose, oxygen, and lactate at rest, during exercise, and in recovery, as well as on muscle glycogen resynthesis. ParticipantsHealthy, lean, young men (n=12). ResultsLeg glucose uptake tended to be two-fold higher at rest (0.22{+/-}0.12mmol/min, P=0.06). Accumulated leg glucose uptake was higher in recovery (21.1{+/-}6mmol, P=0.018) with salbutamol, but not during exercise. Leg oxygen uptake was 80% greater at rest (11{+/-}2.1mmol/min, P<0.01). Accumulated leg oxygen uptake was higher in recovery (1755{+/-}348mL, P<0.01) with salbutamol, but not during exercise. Muscle glycogen was lower with salbutamol 0.5h (109{+/-}25mmol/mg dry-weight, P<0.01) and 5h (101{+/-}19mmol/mg dry-weight, P<0.01) into recovery, suggestive of augmented glycogen utilization during exercise. There was no difference in glycogen resynthesis or glycogen synthase activity in the 5-hour recovery period with salbutamol. ConclusionsThese findings suggest that while resistance exercise confounds the augmentation of leg glucose uptake and metabolic rate induced by beta2-agonist at rest, this suppression is not conserved into recovery from exercise.

physiology↗

bioRxiv2021

High-Intensity Interval Training Remodels the Proteome and Acetylome of Human Skeletal Muscle

Exercise is an effective strategy in the prevention and treatment of metabolic diseases. Alterations in the skeletal muscle proteome, including post-translational modifications, regulate its metabolic adaptations to exercise. Here, we examined the effect of high-intensity interval training (HIIT) on the proteome and acetylome of human skeletal muscle, revealing the response of 3168 proteins and 1263 lysine acetyl-sites on 464 acetylated proteins. We identified global protein adaptations to exercise training involved in metabolism, excitation-contraction coupling, and myofibrillar calcium sensitivity. Furthermore, HIIT increased the acetylation of mitochondrial proteins, particularly those of complex V. We also highlight the regulation of exercise-responsive histone acetyl-sites. These data demonstrate the plasticity of the skeletal muscle proteome and acetylome, providing insight into the regulation of contractile, metabolic and transcriptional processes within skeletal muscle. Herein, we provide a substantial hypothesis-generating resource to stimulate further mechanistic research investigating how exercise improves metabolic health. Impact statementHostrup and colleagues identify global proteomic and acetylomic adaptations to high-intensity interval training, demonstrating adaptations to processes regulating metabolism and contraction.

physiology↗

bioRxiv2018

Cycling with blood flow restriction improves performance and muscle K+ regulation and blunts the effect of antioxidant infusion in humans

We examined if blood flow restriction (BFR) would augment training-induced improvements in muscle K+ handling and performance during intense exercise in men, and if these adaptations would be associated with an effect of muscle antioxidant function on thigh K+ release and with fibre type-dependent modulation of Na+,K+-ATPase-isoform abundance and FXYD1 phosphorylation. Ten recreationally-active men (25 {+/-} 4 y, 49.7 {+/-} 5.3 mL*kg-1*min-1) performed 6 weeks of interval cycling, where one leg trained without (control; CON-leg) and the other leg with BFR (BFR-leg, pressure: 178 mmHg). Before and after training, catheters were inserted into the femoral artery and vein, and blood flow was assessed during single-leg knee-extensions at 25% (Ex1) and 90% of leg peak aerobic power (Ex2) with intravenous infusion of N-acetylcysteine (NAC) or saline (placebo), and a resting muscle biopsy was collected. After training, performance during exhaustive exercise increased to a greater extent in BFR-leg (23%) than in CON-leg (12%, p<0.05), whereas thigh K+ release during Ex2 was attenuated in BFR-leg only (p<0.05). Before training, NAC depressed K+ release during Ex1 (p<0.05), but not during Ex2 (p>0.05). After training, this effect was blunted in BFR-leg (p<0.05), whilst the abundance of Na+,K+-ATPase-isoform 1 in type-II (51%), {beta}1 in type-I (33%), and FXYD1 in type-I (108%) and type-II (60%) fibres was higher in BFR-leg (p<0.05; vs. CON-leg). Thus, interval training with BFR elicits greater improvements in performance and reduces muscle net K+ release during intense exercise, which may be caused by elevated ROS scavenging and fibre type-dependent increases in Na+,K+-ATPase-isoform abundance.\n\nKey pointsO_LIHere, we provide evidence that reactive oxygen species (ROS) play a role in regulating K+ homeostasis in the untrained musculature of humans, as indicated by attenuated thigh K+ efflux during exercise with concomitant antioxidant infusion.\nC_LIO_LIWe also demonstrate that interval training with blood flow restriction (BFR) augments improvements in performance and reduces K+ release from contracting muscles during intense exercise\nC_LIO_LIThe effect of training with BFR on muscle K+ handling appears to be partly mediated by increasing the protection against ROS, since the effect of antioxidant infusion was blunted after training with restricted blood flow.\nC_LIO_LIFurther, training with BFR resulted in higher abundance of Na+,K+-ATPase-isoform 1 in type-II (51%), {beta}1 in type-I (33%), and FXYD1 in type-I (108%) and type-II (60%) muscle fibres. This suggests fibre type-specific adaptations in Na+,K+-ATPase-isoform content are also important for improvements in muscle K+ handling by training with BFR in humans.\nC_LI

physiology↗

bioRxiv2017

Repeated-ischaemic exercise enhances mitochondrial and ion transport gene adaptations in human skeletal muscle: Role of muscle redox state and AMPK

This study assessed the effect of repeated-ischaemic exercise on the mRNA content of PGC-1 (total, 11, and 14) and Na+,K+-ATPase (NKA; 1-3, {beta}1-3, and FXYD1) isoforms in human skeletal muscle, and studied some of the potential molecular mechanisms involved. Eight trained men (26 {+/-} 5 y and 57.4 {+/-} 6.3 mL{middle dot}kg-1{middle dot}min-1) completed three interval running sessions with (ISC) or without ischaemia (CON), or in hypoxia (HYP, ~3250 m), in a randomised, crossover fashion separated by 1 week. A muscle sample was collected from the dominant leg before (Pre) and after exercise (+0h, +3h) in all sessions to measure the mRNA content of PGC-1 and NKA isoforms, oxidative stress markers (i.e. catalase and HSP70 mRNA), muscle lactate, and phosphorylation of AMPK, ACC, CaMKII, and PLB protein in type I and II fibres. Muscle hypoxia (i.e. deoxygenated haemoglobin) was matched between ISC and HYP, which was higher than in CON (~90% vs. ~70%; p< 0.05). The levels of PGC-1 total, -11, -14, and FXYD1 mRNA increased in ISC only (p< 0.05). These changes were associated with increases in oxidative stress markers and higher p-ACCSer221/ACC in type I fibres, but were unrelated to muscle hypoxia, lactate, and CaMKII and PLB phosphorylation. These findings highlight that repeated-ischaemic exercise augments the skeletal muscle gene response related to mitochondrial biogenesis and ion transport in trained men. This effect seems attributable, in part, to increased oxidative stress and AMPK activation, whereas it appears unrelated to altered CaMKII signalling, and the muscle hypoxia and lactate accumulation induced by ischaemia.\n\nSummary in key pointsO_LIWe investigated if ischaemia would augment the exercise-induced mRNA response of PGC-1 and Na+,K+-ATPase (NKA) isoforms (1-3, {beta}1-3, and FXYD1), and examined whether this effect could be related to oxidative stress and fibre type-dependent AMPK and CaMKII signalling in the skeletal muscle of trained men.\nC_LIO_LIRepeated-ischaemic exercise increased the mRNA content of PGC-1 total, -11, and-14, and of the NKA regulatory subunit FXYD1, whereas exercise in systemic hypoxia or alone was without effect on these genes.\nC_LIO_LIThese responses to ischaemia were complemented by increased oxidative stress (as assessed by catalase and HSP70 mRNA) and ACC phosphorylation (an indicator of AMPK activation) in type I fibres. However, they were unrelated to CaMKII signalling, muscle hypoxia, and lactate accumulation.\nC_LIO_LIThus, repeated ischaemic exercise augments the muscle gene response associated with mitochondrial biogenesis and ion homeostasis in trained men. This effect seems partly attributable to promoted oxidative stress and AMPK activation.\nC_LI\n\nAbbreviations

physiology↗

bioRxiv2017

Regulation of Na+,K+-ATPase isoforms and phospholemman (FXYD1) in skeletal muscle fibre types by exercise training and cold-water immersion in men

Little is understood about the fibre type-dependent regulation of Na+,K+-ATPase (NKA) isoforms by exercise training in humans. The main aim of this study was therefore to assess the impact of a period of repeated exercise sessions on NKA-isoform protein abundance in different skeletal muscle fibre types in men. Post-exercise cold-water immersion (CWI) has been reported to increase oxidative stress, which may be one mechanism underlying increases in NKA-isoform expression. Thus, a second aim was to evaluate the effect of CWI on training-induced modulation of NKA-isoform abundance. Vastus lateralis muscle biopsies were obtained from nineteen men at rest before (Pre) and after (Post) six weeks of intense interval cycling, with training sessions followed by passive rest (CON, n=7) or CWI (10{degrees}C; COLD, n=5). Training increased (p<0.05) the abundance of NKA1 and NKA{beta}3 in both type I and type II fibres, NKA{beta}1 in type II fibres, but was without effect on NKA2 and NKA3 (p>0.05). Furthermore, training decreased FXYD1 protein content in type I fibres, which abolished its fibre type-specific expression detected at Pre (p<0.05). CWI was without impact on the responses to training (p>0.05). These results highlight that NKA isoforms are regulated in a fibre type-dependent fashion in response to intense training in humans. This may partly explain the improvement in muscle Na+/K+ handling after a period of intense training. CWI may be performed without adversely or favourably affecting training-induced changes in NKA-isoform abundance.\n\nSummary in key pointsO_LIIt is unclear how Na+,K+-ATPase (NKA) isoforms are regulated in different skeletal muscle fibre types by exercise training in humans, and the effect on phospholemman (FXYD1) protein abundance in different fibre types remains to be elucidated. We investigated the impact of six weeks of training on NKA-isoform protein abundance (1-3, {beta}1-3 and FXYD1) in type I and II muscle fibres in men.\nC_LIO_LIWe show that intense interval training selectively increases the protein content of NKA 1 and {beta}3 in both fibre types, {beta}1 in type II fibres, and decreases FXYD1 in type I fibres.\nC_LIO_LIThese results suggest the favourable impact of intense training on human muscle Na+/K+ regulation could be attributable, in part, to fibre type-dependent modulation of NKA-isoform abundance.\nC_LIO_LIGiven that cold exposure has been shown to modulate cellular redox state, which has been linked to increased NKA expression, we also investigated the effect of exercise training plus cold-water immersion (CWI) on the fibre type-specific responses of NKA isoforms and FXYD1. We found that CWI was without effect on the responses to training.\nC_LI\n\nAbbreviationsAMPK{beta}2, 5 AMP-activated protein kinase subunit {beta}2; CaMKII, Ca2+-calmodulin-dependent protein kinase isoform 2; COLD, cold-water immersion group; CON, control group; Ct, cycle threshold; CV, coefficient of variation; CWI, cold-water immersion; EDL, extensor digitorum longus; FXYD1, phospholemman isoform 1; HSP70, heat-shock protein 70; GXT, graded exercise test; K+, potassium; Km, Michaelis-Menten constant; MHC, myosin heavy chain; Na+, sodium; NF-1, neurofibromatosis type 1; NKA, Na+,K+-ATPase; ROS, reactive oxygen species; SDS-PAGE, sodium dodecyl sulphate polyacrylamide gel electrophoresis; SERCA1, sarco/endoplasmic reticulum Ca2+-ATPase isoform 1; VO2peak, maximum oxygen uptake.

physiology↗

bioRxiv2017

Post-exercise cold-water immersion increases Na+,K+-ATPase α2-isoform mRNA content in parallel with elevated Sp1 expression in human skeletal muscle

We investigated the effect of a session of sprint-interval exercise on the mRNA content of NKA isoforms (1-3, {beta}1-3) and FXYD1 in human skeletal muscle. To explore some of the cellular stressors involved in this regulation, we evaluated the association between these mRNA responses and those of the transcription factors Sp1, Sp3 and HIF-1. Given cold exposure perturbs muscle redox homeostasis, which may be one mechanism important for increases in NKA-isoform mRNA, we also explored the effect of post-exercise cold-water immersion (CWI) on the mRNA responses. Muscle was sampled from nineteen men before (Pre) and after (+0h, +3h) exercise plus passive rest (CON, n=10) or CWI (10{degrees}C; COLD, n=9). In COLD, exercise increased NKA2 and Sp1 mRNA (+0h, p<0.05). These genes remained unchanged in CON (p>0.05). In both conditions, exercise increased NKA1, NKA{beta}3 and HIF-1 mRNA (+3h; p <0.05), decreased NKA{beta}2 mRNA (+3h; p<0.05), whereas NKA3, NKA{beta}1, FXYD1 and Sp3 mRNA remained unchanged (p>0.05). These human findings highlight 1) sprint-interval exercise increases the mRNA content of NKA 1 and {beta}3, and decreases that of NKA {beta}2, which may relate, in part, to exercise-induced muscle hypoxia, and 2) post-exercise CWI augments NKA2 mRNA, which may be associated with promoted Sp1 activation.

physiology↗