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Potential Role of TBC1D4 in Enhanced Post-Exercise Insulin Action in Human Skeletal Muscle

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Potential Role of TBC1D4 in Enhanced Post-Exercise Insulin Action in Human Skeletal Muscle Diabetologia (2009) 52:891–900 DOI 10.1007/s00125-009-1294-y ARTICLE Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle J. T. Treebak & C. Frøsig & C. Pehmøller & S. Chen & S. J. Maarbjerg & N. Brandt & C. MacKintosh & J. R. Zierath & D. G. Hardie & B. Kiens & E. A. Richter & H. Pilegaard & J. F. P. Wojtaszewski Received: 19 January 2009 /Accepted: 22 January 2009 /Published online: 28 February 2009 # Springer-Verlag 2009 Abstract Methods Insulin-regulated glucose metabolism was evalu- Aims/hypothesis TBC1 domain family, member 4 (TBC1D4; ated in 12 healthy moderately trained young men 4 h after also known as AS160) is a cellular signalling intermediate to one-legged exercise at basal and during a euglycaemic– glucose transport regulated by insulin-dependent and hyperinsulinaemic clamp. Vastus lateralis biopsies were -independent mechanisms. Skeletal muscle insulin sensitivity taken before and immediately after the clamp. is increased after acute exercise by an unknown mechanism Results Insulin stimulation increased glucose uptake in that does not involve modulation at proximal insulin both legs, with greater effects (~80%, p<0.01) in the signalling intermediates. We hypothesised that signalling previously exercised leg. TBC1D4 phosphorylation, through TBC1D4 is involved in this effect of exercise as it is assessed using the phospho–AKT (protein kinase B) a common signalling element for insulin and exercise. substrate antibody and phospho- and site-specific anti- bodies targeting six phosphorylation sites on TBC1D4, increased at similar degrees to insulin stimulation in the previously exercised and rested legs (p<0.01). However, J. T. Treebak : C. Frøsig : C. Pehmøller : S. J. Maarbjerg : N. Brandt : B. Kiens : E. A. Richter : J. F. P. Wojtaszewski (*) TBC1D4 phosphorylation on Ser-318, Ser-341, Ser-588 Copenhagen Muscle Research Centre, Molecular Physiology and Ser-751 was higher in the previously exercised leg, Group, Department of Exercise and Sport Sciences, both in the absence and in the presence of insulin (p<0.01; University of Copenhagen, Ser-588, p=0.09; observed power=0.39). 14–3–3 binding DK-2100 Copenhagen, Denmark e-mail: [email protected] capacity for TBC1D4 increased equally (p<0.01) in both : legs during insulin stimulation. S. Chen C. MacKintosh Conclusion/interpretation We provide evidence for site- MRC Protein Phosphorylation Unit, College of Life Sciences, specific phosphorylation of TBC1D4 in human skeletal University of Dundee, Dundee, Scotland, UK muscle in response to physiological hyperinsulinaemia. The data support the idea that TBC1D4 is a nexus for J. R. Zierath insulin- and exercise-responsive signals that may mediate Section for Integrative Physiology, Department of Molecular increased insulin action after exercise. Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden Keywords AKT substrate of 160 kDa . AS160 . D. G. Hardie Glucose metabolism . TBC1D1 Division of Molecular Physiology, College of Life Sciences, University of Dundee, Dundee, Scotland, UK Abbreviations AKT Protein kinase B H. Pilegaard AMPK AMP-activated kinase Copenhagen Muscle Research Centre and Centre of Inflammation GAP GTPase-activating proteins and Metabolism, Department of Biology, University of Copenhagen, PAS Phospho-AKT substrate Copenhagen, Denmark PVDF Polyvinylidene fluoride 892 Diabetologia (2009) 52:891–900 TBC1D1 TBC1 domain family, member 1 skeletal muscle has shown that prior exercise resulted in TBC1D4 TBC1 domain family, member 4 enhanced basal and insulin-stimulated glucose uptake and phosphorylation of TBC1D4 [26], no such evidence has been generated in humans. Introduction Phosphorylation of TBC1D1 and TBC1D4 has previ- ously been evaluated using the phospho-AKT substrate Insulin sensitivity of skeletal muscle to stimulate glucose (PAS) antibody, which recognises phosphorylation sites on uptake is markedly enhanced by a prior bout of exercise. AKT substrates lying in a (R/K)X(R/K)XXS*/T* sequence This effect is restricted to the previously contracted muscle, motif. Thus, the interpretation of previous investigations rather than a consequence of changes in systemic factors has been limited by the unselective nature of the PAS [1–8]. The enhanced insulin sensitivity that increases antibody, which may recognise multiple phosphorylation glucose transport after acute exercise is associated with sites on TBC1D1 and TBC1D4 and mask potential site- recruitment of GLUT4 molecules to the plasma membrane specific effects of exercise or insulin. It was recently [9], but not with GLUT4 protein levels [10]. This effect shown, however, that only Thr-642 on TBC1D4 and Thr- cannot be linked to increased signal transduction at the 596 on TBC1D1 are recognised by the PAS antibody [13, insulin receptor or intermediates in proximal components of 18, 19], leaving several phosphorylation sites that are the insulin signalling cascade involving IRS1, phosphoino- potentially important for GAP activity unrecognised. sitide 3-kinase, AKT (protein kinase B) and glycogen Furthermore, since TBC1D1 and TBC1D4 have similar synthase kinase 3 [8, 10, 11]. mobility on SDS-PAGE and since both proteins are TBC1 domain family, member 1 (TBC1D1) and member recognised by the PAS antibody, data from previous 4 (TBC1D4) are GTPase-activating proteins (GAP) and investigations using this antibody should be interpreted direct targets of AKT [12, 13]. They are similar in size and carefully [12, 21, 22, 29–35]. To circumvent these prob- structure and run at approximately 150 to 160 kDa during lems, we used phospho-specific antibodies against six SDS-PAGE [14]. The GAP domain of both TBC1D1 and phosphorylation sites on TBC1D4. Our findings suggest TBC1D4 stimulates the GTPase activity of certain Rab that site-specific TBC1D4 phosphorylation events may play proteins, thereby inhibiting GLUT4 translocation to the a role in mediating the beneficial effects of exercise on plasma membrane [13, 15, 16]. GTPase activity is thought skeletal muscle insulin action. to be regulated by phosphorylation and both TBC1D1 and TBC1D4 proteins contain multiple Ser/Thr residues that can be phosphorylated by various kinases [13, 14, 17]. In Methods line with this, stimulation by aminoimidazole carboxamide ribonucleotide, insulin and other growth factors, as well as Participants The participants in this study were 12 young, contraction of skeletal muscle, leads to phosphorylation of healthy men (age 24±1 years; weight 80±2.7 kg; height 2 TBC1D1 and/or TBC1D4 [18–22]. Beside phosphoryla- 188±2 cm; BMI 23±0.5 kg/m ;VO2peak 4.6±0.1 l/min), tion, binding of 14–3–3 proteins to phosphorylated Thr-642 who gave informed consent to participate. The study was and/or Ser-341 of TBC1D4 [18, 23] is important for approved by the local Ethics Committee in the municipality glucose transport in 3T3-L1 adipocytes possibly via of Copenhagen (01-180/01) and performed in accordance regulation of the GAP domain [23]. with the Helsinki declaration. Being multi-kinase substrates, TBC1D1 and TBC1D4 may be a point of convergence for insulin-dependent and Experimental design Following 4 days of standardised diet insulin-independent signalling pathways regulating glucose (65% of energy as carbohydrate, 20% as fat, 15% as transport in skeletal muscle. Indeed, both insulin- and protein) the participants arrived at the laboratory in the contraction-induced glucose uptake in skeletal muscle have morning after an overnight fast. They ate a small, been shown to partly depend on TBC1D4 [24]. Conse- carbohydrate-rich snack (5% daily energy intake) and then quently, the intracellular signals emanating from the performed 60 min of dynamic one-legged knee extensor contracting muscle during exercise may interact with the exercise (one kick/s) at ˜80% of peak workload of the knee insulin signalling pathway at the TBC1D1 or TBC1D4 extensors [8]. During the 60 min of exercise, two 5 min level, thereby mediating enhanced glucose uptake in phases at 100% of peak workload were performed to ensure previously exercised muscle [25]. Recent studies of rodent activation of the majority of the vastus lateralis muscle. The and human skeletal muscle provide evidence for a role of contralateral leg was kept at rest. After exercise, partic- TBC1D4 in this respect [26–28], showing that TBC1D4 ipants rested in the supine position for 4 h. During the phosphorylation is increased in the hours following an resting period participants had Teflon catheters inserted acute bout of exercise. However, although one study in rat below the inguinal ligament in one femoral artery and both Diabetologia (2009) 52:891–900 893 femoral veins and after 4 h of rest a 100 min euglycaemic– the TBC1D4 phospho-specific antibodies and the TBC1D1 hyperinsulinaemic clamp (9 nmol min−1 kg−1) was per- antibody has been confirmed using various cell lines [18, formed as described previously [11]. Before and immedi- 19]. To further confirm specificity of the TBC1D4 ately after the clamp, biopsies from the vastus lateralis phospho-specific antibodies, we performed immunodeple- muscle were taken under subcutaneous anaesthesia (~2– tion analyses using TBC1D1 and TBC1D4 antibodies and 3 ml xylocain [10 mg/ml lidocaine]; AstraZeneca, Söder- muscle lysates from human skeletal muscle. tälje, Sweden) from the rested and exercised leg using individual incisions. Specifically, to address mRNA iso- Immunoprecipitation of TBC1D4 and TBC1D1 TBC1D4 form expression of TBC1D1 and TBC1D4, biopsies were and TBC1D1 were immunoprecipitated
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