Jesper Bratz BirkUniversity of Copenhagen · Department of Nutrition, Exercise and Sports
Jesper Bratz Birk
MS
About
71
Publications
11,825
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
4,585
Citations
Introduction
Additional affiliations
April 2018 - January 2019
June 2001 - present
May 2000 - June 2001
Publications
Publications (71)
Objective:
Skeletal muscle is an attractive target for blood glucose-lowering pharmacological interventions. Oral dosing of small molecule direct pan-activators of AMPK, that bind to the Allosteric Drug and Metabolite (ADaM) site, lowers blood glucose through effects in skeletal muscle. The molecular mechanisms responsible for this effect are not...
Key points:
Tamoxifen-inducible skeletal muscle-specific AXIN1 knockout (AXIN1 imKO) in mouse does not affect whole-body energy substrate metabolism. AXIN1 imKO does not affect AICAR or insulin-stimulated glucose uptake in adult skeletal muscle AXIN1 imKO does not affect adult skeletal muscle AMPK or mTORC1 signaling during AICAR/insulin/amino aci...
A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22015-4
Key points:
Rodent studies suggest muscle fibre type-specific insulin response in the recovery from exercise. The current study investigates muscle fibre type-specific insulin action in the recovery from exercise in healthy subjects. In type I and type II muscle fibres, key proteins in glucose metabolism are similarly regulated by insulin during r...
The present study compared the effects of post exercise carbohydrate plus protein (CHO+PROT) and carbohydrate (CHO) only supplementation on muscle glycogen metabolism, anabolic cell signalling and subsequent exercise performance. Nine endurance-trained males cycled twice to exhaustion (muscle glycogen decreased from ~495 to ~125 mmol·kg dw ⁻¹ ) and...
Objective
Current evidence for AMPK-mediated regulation of skeletal muscle metabolism during exercise is mainly based on transgenic mouse models with chronic (lifelong) disruption of AMPK function. Findings based on such models are potentially biased by secondary effects related to chronic lack of AMPK function. In an attempt to study the direct ef...
A single bout of exercise enhances insulin action in the exercised muscle. However, not all human studies find that this translates into increased whole-body insulin action, suggesting that insulin action in rested muscle or other organs may be decreased by exercise. To investigate this, eight healthy men underwent a euglycemic hyperinsulinemic cla...
5´AMP–activated protein kinase (AMPK) is a mediator of a healthy metabolic phenotype in skeletal muscle. Metformin may exacerbate the energy disturbances observed during exercise leading to enhanced AMPK activation, and these disturbances may provoke early muscular fatigue. We studied acute (1 day) and short‐term (4 days) effects of metformin treat...
Exercise increases glucose uptake in skeletal muscle independently of insulin signaling. This makes exercise an effective stimulus to increase glucose uptake in insulin-resistant skeletal muscle. AMPK has been suggested to regulate muscle glucose uptake during exercise/contraction, but findings from studies of various AMPK transgenic animals have n...
The ADAMTS9 rs4607103 C allele is one of the few gene variants proposed to increase the risk of type 2 diabetes through an impairment of insulin sensitivity. We show that the variant is associated with increased expression of the secreted ADAMTS9 and decreased insulin sensitivity and signaling in human skeletal muscle. In line with this, mice lacki...
Keypoints:
A single bout of exercise is capable of increasing insulin sensitivity in human skeletal muscle. Whether this ability is affected by training status is not clear. Studies in mice suggest that the AMPK-TBC1D4 signalling axis is important for the increased insulin-stimulated glucose uptake after a single bout of exercise. This study is th...
Supplemental Table S1: Proteomic analyses of targeted proteins involved in glucose uptake, glycolysis, TCA Cycle, fatty acid β-oxidation, PDH and oxidative phosphorylation. Data are presented as log2 ratio for exercise leg relative to resting leg (Ex/Re) (n = 5). The number observations for up- and down-regulation of proteins are indicated by arrow...
Supplemental III: Full List of Human Muscle MS repository. Quantification of peptides is given as log2 ratio for exercise leg relative to resting leg (Ex/Re) (n = 5). Supplemental II provides a full list of proteins detected and is presented as log2 ratio for the exercised leg relative to the rested control leg.
Supplemental I: Supplemental Experimental Procedures. Supplemental I provides a detailed description of experimental procedures and analyses applied in the human one-legged glycogen supercompensation study and animal experiments.
Objective:
A single bout of exercise followed by intake of carbohydrates leads to glycogen supercompensation in prior exercised muscle. Our objective was to illuminate molecular mechanisms underlying this phenomenon in skeletal muscle of man.
Methods:
We studied the temporal regulation of glycogen supercompensation in human skeletal muscle durin...
The 5′-AMP-activated protein kinase is a complicated enzyme consisting of three different subunits, each of which is expressed as two or three isoforms. This gives the possibility of 12 different heterotrimeric complexes, which could have diverse functions within the cell. To map out which of these complexes are present and to what extent in skelet...
Measuring the kinase activity of the 5′-AMP-activated protein kinase (AMPK) is an essential part of understanding the regulation of this metabolic master switch. The AMPK heterotrimer can exist in 12 different constellations with potentially diverse activation patterns. It is therefore important to be able to measure heterotrimer-specific activity...
We hypothesised that skeletal muscles of healthy young people have a large variation in oxidative capacity and fibre-type composition, and aimed therefore to investigate glucose metabolism in biopsies and myotubes isolated from musculus vastus lateralis from healthy males with varying degrees of maximal oxygen uptake. Trained and intermediary train...
Exercise training repeatedly exposes skeletal muscle to cyclical periods of glycogen depletion and re-synthesis. There is evidence to suggest that signal transduction pathways central in driving exercise adaptation are enhanced when exercise is performed in a glycogen depletion state. The purpose of the current study was to use exercise and carbohy...
Earlier studies have demonstrated that muscle insulin sensitivity to stimulate glucose uptake is enhanced several hours after an acute bout of exercise. Using 5-aminoimidazole-4-carboxamide-ribonucleotide (AICAR), we recently demonstrated that prior activation of AMPK is sufficient to increase insulin sensitivity in mouse skeletal muscle. Here we a...
Current evidence on exercise-mediated AMPK regulation in skeletal muscle of type 2 diabetic (T2D) patients is inconclusive. This may relate to inadequate segregation of trimer complexes in the investigation of AMPK activity. We examined the regulation of AMPK and downstream targets ACCβ, TBC1D1 and TBC1D4 in muscle biopsies obtained from thirteen o...
Key points:
This study aimed to provide molecular insight into the differential effects of age and physical inactivity on the regulation of substrate metabolism during moderate-intensity exercise. Using the arteriovenous balance technique, we studied the effect of immobilization of one leg for 2 weeks on leg substrate utilization in young and olde...
Exercise training increases skeletal muscle expression of metabolic proteins improving the oxidative capacity. Adaptations in skeletal muscle by pharmacologically induced activation of 5'AMP-activated protein kinase (AMPK) are dependent on the AMPKα2 subunit. We hypothesized that exercise training-induced increases in exercise capacity and expressi...
AMP-activated protein kinase (AMPK) is a regulator of energy homeostasis during exercise. Studies suggest muscle fibre type-specific AMPK expression. However, fibre type-specific regulation of AMPK and downstream targets during exercise has not been proven. We hypothesized that AMPK subunits are expressed in a fibre type-dependent manner and that f...
The importance of AMPK in regulation of fatty acid (FA) oxidation in skeletal muscle with contraction/exercise is unresolved. Using a mouse model lacking both AMPKα1 and -α2 in skeletal muscle specifically (mdKO), we hypothesized that FA utilization would be impaired in skeletal muscle. AMPKα mdKO mice displayed normal respiratory exchange ratio (R...
Acute exercise increases glucose uptake in skeletal muscle by an insulin-independent mechanism. In the period after exercise insulin sensitivity to increase glucose uptake is enhanced. The molecular mechanisms underpinning this phenomenon are poorly understood, but appear to involve an increased cell surface abundance of GLUT4. While increased prox...
Skeletal muscle is a heterogeneous tissue composed of different fiber types. Studies suggest that insulin-mediated glucose metabolism is different between muscle fiber types. We hypothesized that differences are due to fiber-type specific expression/regulation of insulin signaling elements and/or metabolic enzymes. Pools of type I and II fibers wer...
Key points
Phosphorylation signature patterns on TBC1D1 and TBC1D4 proteins in the insulin–glucose pathway were investigated in human skeletal muscle in response to physiological insulin and exercise.
In response to postprandial increase in insulin, Akt phosphorylation of T308 and S473 correlated significantly with sites on TBC1D1 (T596) and TBC1D4...
Subjects with a low birth weight (LBW) display increased risk of developing type 2 diabetes (T2D). We hypothesized that this is associated with defects in muscle adaptations following acute and regular physical activity, evident by impairments in the exercise-induced activation of AMPK signaling. We investigated 21 LBW and 21 normal birth weight (N...
AMP activated protein kinase (AMPK) is a heterotrimeric αβγ complex. Selective pharmacological activation of specific AMPK‐complexes through targeting of its regulatory subunits is an attractive strategy to confine AMPK activation to select tissues to combat diseases such as type 2 Diabetes. Furthermore, it is a useful tool to study specific AMPK c...
Type 2 diabetes is characterized by reduced muscle glycogen synthesis. The key enzyme in this process, glycogen synthase (GS), is activated via proximal insulin signaling, but the exact molecular events remain unknown. We previously demonstrated that phosphorylation of Threonine-308 on Akt (pAkt-T308), Akt2 activity, and GS activity in muscle were...
Excess lipid availability causes insulin resistance. We examined the effect of acute exercise on lipid-induced insulin resistance and TBC1 domain family member 1/4 (TBCD1/4)-related signaling in skeletal muscle. In eight healthy young male subjects, 1 h of one-legged knee-extensor exercise was followed by 7 h of saline or intralipid infusion. Durin...
The energy/fuel sensor 5'-AMP-activated protein kinase (AMPK) is viewed as a master regulator of cellular energy balance due to its many roles in glucose, lipid, and protein metabolism. In this review we focus on the regulation of AMPK activity in skeletal muscle and its involvement in glucose metabolism, including glucose transport and glycogen sy...
In type 2 diabetes, reduced insulin-stimulated glucose disposal, primarily glycogen synthesis, is associated with defective insulin activation of glycogen synthase (GS) in skeletal muscle. Hyperglycaemia may compensate for these defects, but to what extent it involves improved insulin signalling to glycogen synthesis remains to be clarified.
Whole-...
The aim of this study was to investigate the molecular mechanisms regulating FA translocase CD36 (FAT/CD36) translocation and FA uptake in skeletal muscle during contractions. In one model, wild-type (WT) and AMP-dependent protein kinase kinase dead (AMPK KD) mice were exercised or extensor digitorum longus (EDL) and soleus (SOL) muscles were contr...
Phosphorylation of Ser318 (a), Ser341 (b), Ser588 (c), Thr642 (d) and Ser751 (e), and PAS phosphorylation (f) expressed in relation to total TBC1D4 protein content (arbitrary units [AU]). Measurements were performed in skeletal muscle biopsies obtained from type 2 diabetic (T2D) and control (CON) participants during the basal (white bars) and insul...
TBC1D1 is a Rab-GTPase activating protein involved in regulation of GLUT4 translocation in skeletal muscle. We here evaluated exercise-induced regulation of TBC1D1 Ser237 phosphorylation and 14-3-3 protein binding capacity in human skeletal muscle. In separate experiments healthy men performed all-out cycle exercise lasting either 30 s, 2 min or 2...
Insulin-mediated glucose disposal rates (R(d)) are reduced in type 2 diabetic patients, a process in which intrinsic signalling defects are thought to be involved. Phosphorylation of TBC1 domain family, member 4 (TBC1D4) is at present the most distal insulin receptor signalling event linked to glucose transport. In this study, we examined insulin a...
We have previously shown that overnight fasted women have higher insulin-stimulated whole body and leg glucose uptake despite a higher intramyocellular triacylglycerol concentration than men. Women also express higher muscle mRNA levels of proteins related to lipid metabolism than men. We therefore hypothesized that women would be less prone to lip...
Insulin resistance in skeletal muscle is a key factor in the development of type 2 diabetes and although some studies indicate that this could be partly attributed to reduced content and activity of various proximal and distal insulin signalling molecules, consensus is lacking. We therefore aimed to investigate the regulation of proximal insulin si...
Insulin-stimulated glucose disposal is impaired in obesity and type 2 diabetes mellitus (T2DM) and is tightly linked to impaired skeletal muscle glucose uptake and storage. Impaired activation of glycogen synthase (GS) by insulin is a well-established defect in both obesity and T2DM, but the underlying mechanisms remain unclear.
Insulin action was...
To test the hypothesis that free fatty acid (FFA) and muscle glycogen modify exercise-induced regulation of PDH (pyruvate dehydrogenase) in human skeletal muscle through regulation of PDK4 expression.
On two occasions, healthy male subjects lowered (by exercise) muscle glycogen in one leg (LOW) relative to the contra-lateral leg (CON) the day befor...
Some studies suggest that the 5'-AMP-activated protein kinase (AMPK) is important in regulating muscle glucose uptake in response to intense electrically stimulated contractions. However, it is unknown whether AMPK regulates muscle glucose uptake during in vivo exercise. We studied this in male and female mice overexpressing kinase-dead AMPKalpha2...
The protein complex AMP-activated protein kinase (AMPK) is believed to play an important role in the regulation of skeletal muscle glucose and lipid metabolism. Defects in the AMPK system might therefore be an important factor in the pathogenesis of type 2 diabetes. We aimed to identify genetic and environmental mechanisms involved in the regulatio...
5'-AMP-activated protein kinase (AMPK) regulates several aspects of metabolism. Recently, A-769662 was shown to activate AMPK in skeletal muscle. However, no biological effects of AMPK activation by A-769662 in this tissue have been reported. We hypothesized that A-769662 would increase glucose uptake in skeletal muscle. We studied incubated soleus...
TBC1D1 is a Rab-GTPase-activating protein (GAP) known to be phosphorylated in response to insulin, growth factors, pharmacological agonists that activate 5'-AMP-activated protein kinase (AMPK), and muscle contraction. Silencing TBC1D1 in L6 muscle cells by siRNA increases insulin-stimulated GLUT4 translocation, and overexpression of TBC1D1 in 3T3-L...
This study evaluated whether improved insulin-stimulated glucose uptake in recovery from acute exercise coincides with reduced malonyl-CoA (MCoA) content in human muscle. Furthermore, we investigated whether a high-fat diet [65 energy-% (Fat)] would alter the content of MCoA and insulin action compared with a high-carbohydrate diet [65 energy-% (CH...
Insulin resistance in skeletal muscle is a major risk factor for type 2 diabetes in women with polycystic ovary syndrome (PCOS). However, the molecular mechanisms underlying skeletal muscle insulin resistance and the insulin-sensitizing effect of thiazolidinediones in PCOS in vivo are less well characterized.
We determined molecular mediators of in...
5'AMP-activated protein kinase (AMPK) exists as a heterotrimer comprising a catalytic alpha subunit and regulatory beta and gamma subunits. The AMPK system is activated under conditions of cellular stress, indicated by an increase in the AMP/ATP ratio, as observed, e.g. in muscles during contractile activity. AMPK was originally thought to be activ...
To test the hypothesis that pyruvate dehydrogenase (PDH) is differentially regulated in specific human muscles, regulation of PDH was examined in triceps, deltoid, and vastus lateralis at rest and during intense exercise. To elicit considerable glycogen use, subjects performed 30 min of exhaustive arm cycling on two occasions and leg cycling exerci...
We investigated time- and intensity-dependent effects of exercise on phosphorylation of Akt substrate of 160 kDa (AS160) in human skeletal muscle. Subjects performed cycle exercise for 90 min (67% VO2 peak, n=8), 20 min (80% VO2 peak, n=11), 2 min (110% of peak work rate, n=9), or 30 s (maximal sprint, n=10). Muscle biopsies were obtained before, d...
5'AMP-activated protein kinase (AMPK) is a key regulator of cellular metabolism and is regulated in muscle during exercise. We have previously established that only three of 12 possible AMPK alpha/beta/gamma-heterotrimers are present in human skeletal muscle. Previous studies describe discrepancies between total AMPK activity and regulation of its...
To investigate pyruvate dehydrogenase (PDH)-E1alpha subunit phosphorylation and whether free fatty acids (FFAs) regulate PDH activity, seven subjects completed two trials: saline (control) and intralipid/heparin (intralipid). Each infusion trial consisted of a 4-h rest followed by a 3-h two-legged knee extensor exercise at moderate intensity. Durin...
Recently we reported the coexistence of postprandial hypoglycaemia and moderate insulin resistance in heterozygous carriers of the Arg1174Gln mutation in the insulin receptor gene (INSR). Controlled studies of in vivo insulin signalling in humans with mutant INSR are unavailable, and therefore the cellular mechanisms underlying insulin resistance i...
5'-AMP-activated protein kinase (AMPK) has been suggested to be a 'metabolic master switch' regulating various aspects of muscle glucose and fat metabolism. In isolated rat skeletal muscle, glucose suppresses the activity of AMPK and in human muscle glycogen loading decreases exercise-induced AMPK activation. We hypothesized that oral glucose inges...
We tested the hypothesis that 5'AMP-activated protein kinase (AMPK) plays an important role in regulating the acute, exercise-induced activation of metabolic genes in skeletal muscle, which were dissected from whole-body alpha2- and alpha1-AMPK knockout (KO) and wild-type (WT) mice at rest, after treadmill running (90 min), and in recovery. Running...
Strength training enhances insulin sensitivity and represents an alternative to endurance training for patients with type 2 diabetes (T2DM). The 5'AMP-activated protein kinase (AMPK) may mediate adaptations in skeletal muscle in response to exercise training; however, little is known about adaptations within the AMPK system itself. We investigated...
The 5'AMP-activated protein kinase (AMPK) is a potential antidiabetic drug target. Here we show that the pharmacological activation of AMPK by 5-aminoimidazole-1-beta-4-carboxamide ribofuranoside (AICAR) leads to inactivation of glycogen synthase (GS) and phosphorylation of GS at Ser 7 (site 2). In muscle of mice with targeted deletion of the alpha...
Contraction-induced glucose uptake in skeletal muscle is mediated by an insulin-independent mechanism that leads to translocation of the GLUT4 glucose transporter to the muscle surface membrane from an intracellular storage site. Although the signalling events that increase glucose transport in response to muscle contraction are not fully elucidate...
Human papillomavirus type 16 (HPV-16) is the major risk factor for development of cervical cancer. The major oncoprotein E7 enhances cell growth control. However, E7 has in some reports been shown to induce apoptosis suggesting that there is a delicate balance between cell proliferation and induction of cell death. We have used the osteosarcoma cel...
We investigated the importance of the two catalytic alpha-isoforms of the 5'-AMP-activated protein kinase (AMPK) in 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) and contraction-induced glucose uptake in skeletal muscle. Incubated soleus and EDL muscle from whole-body alpha2- or alpha1-AMPK knockout (KO) and wild type (WT) mice wer...
The AMPK (5'AMP-activated protein kinase) is becoming recognized as a critical regulator of energy metabolism. However, many of these effects in muscle metabolism have been ascribed to AMPK based on the use of the unspecific activator AICAR (5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside). Using mouse models in which AMPK activity has been...
After the discovery and clinical use of insulin for treatment of diabetes it became clear that some of the biological effect of insulin was dependent on the circumstances under which it was given. Relevant for this review is the notion that physical activity, in addition to its own direct metabolic effects also markedly affects the ability of insul...
Questions
Question (1)
If you're doing kinase activity assays the old fashion way with radioactive labelled ATP and peptide substrate you might use P81 cation exchange chromatography paper to capture the peptide. Whatman, now GE Healtcare has stopped the production and I can't find anywhere to buy this P81 paper anymore. I figure that if everybody who is in need of this product contacts GE Healthcare and ask them to start production again, we might get them to do it. So please help.
