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1 The Centre of Inflammation and Metabolism at Department of Infectious Diseases and Copenhagen Muscle Research Center, Rigshospitalet and Faculty of Health Sciences, University of Copenhagen, Denmark 2 Section of Neuroprotection, Institute of Neurobiology and Molecular Pharmacology, Faculty of Health Sciences, University of Copenhagen, Denmark
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(Received 9 July 2006;
accepted after revision 5 October 2006; first published online 9 October 2006)
Corresponding author B. K. Pedersen: Centre of Inflammation and Metabolism, Rigshospitalet – Section 7641, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. Email: bkp{at}rh.dk
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(TNF-), interleukin (IL)-6, IL-8 and IL-15 (Chan et al. 2004). Among these cytokines, solid evidence exists that IL-6 (Pedersen et al. 2003a,b; Febbraio & Pedersen, 2002, 2005) and IL-8 (Nieman et al. 2003; Chan et al. 2004; Akerstrom et al. 2005) are regulated by exercise, at the levels of both mRNA and protein. Interleukin-6 and IL-8 are released from working skeletal muscle. Muscle-derived IL-6 (Steensberg et al. 2000) is released in significant quantities into the systemic circulation, whereas only a small transient net release of IL-8 is found from working muscle. This small release of IL-8 does not result in an increase in the systemic plasma concentrations of IL-8, suggesting that muscle-derived IL-8 might have a local effect (Akerstrom et al. 2005). Interkeukin-8 was originally identified as a chemotactic factor secreted by activated monocytes and macrophages that promote directional migration of leucocytes (Baggiolini et al. 1989). However, IL-8 possesses biological functions in addition to and distinct from its role in regulating inflammatory responses. Interkeukin-8 is a member of the CXC chemokine family, which is defined by four highly conserved cysteine amino acid residues, with the first two cysteines separated by one non-conserved amino acid residue. The subfamily can be further subclassified by the presence of a characteristic three amino acid motif, Glu-Leu-Arg (ELR motif), at the NH2-terminus before the first cysteine amino acid. The family members that contain the ELR motif (CXC ELR+) are potent promoters of angiogenesis, and IL-8 has been shown to induce endothelial cell chemotaxis in vitro and to induce angiogenesis in vivo (Koch et al. 1992; Strieter et al. 1992, 1995; Norrby, 1996; Bek et al. 2002). In contrast, CXC chemokines that lack the ELR motif (CXC ELR–) are inhibitors of angiogenesis (Strieter et al. 2005). Two homologous chemokine receptors, the CXC receptors 1 and 2 (CXCR1 and CXCR2), bind IL-8 with high affinity (Belperio et al. 2000). Interleukin-8 mediates its chemotactic effects via CXCR1, whereas CXCR2 is expressed by human microvascular endothelial cells and is considered to be the receptor responsible for IL-8-induced angiogenesis (Addison et al. 2000; Heidemann et al. 2003). The importance of CXCR2-mediated angiogenesis in vivo is further demonstrated by the lack of angiogenic activity induced by ELR+ CXC chemokines in the presence of neutralizing antibodies to CXCR2 in the rat corneal micropocket assay and in the corneas of CXCR2–/– mice (Addison et al. 2000). The receptors for IL-8, CXCR1 and CXCR2, are widely expressed on normal and various tumour cells (Yang et al. 1997; Smith et al. 1994; Singh et al. 1999; Inoue et al. 2000) and bind IL-8 with high affinity (Holmes et al. 1991; Cerretti et al. 1993; Baggiolini et al. 1997; Wang et al. 1998). Angiogenic factors that are regulated in skeletal muscle by exercise include vascular endothelial growth factor (VEGF; Prior et al. 2004) and transforming growth factor-ß (TGF-ß; Gavin & Wagner, 2001).
Given that IL-8 is a potent angiogenic factor in several tissues, we propose a role for skeletal muscle-derived IL-8 in the stimulation of angiogenesis in response to exercise. In the present study, we investigated whether the IL-8 receptor CXCR2 is expressed in human skeletal muscle and whether the expression is regulated by exercise. In addition, we analysed the cellular localization of the CXCR2 protein and its colocalization with the accessory TGF-ß receptor, endoglin (CD105). Endoglin is reported to be predominantly expressed on activated endothelial cells, and its expression is potently induced by hypoxia (Miller et al. 1999; Sanchez-Elsner et al. 2002; Fonsatti et al. 2003). Consistently, elevated levels of endoglin have been detected on vascular endothelial cells in tissues undergoing active angiogenesis, such as regenerating tissues and inflamed tissues or tumours (Wang et al. 1994; Krupinski et al. 1994; Miller et al. 1999; Torsney et al. 2002).
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Subjects.
Fifteen men, all non smokers, with a mean (±
S.D.) age, height, weight and body mass index (BMI) of 24.9 ± 4 years, 180.9 ± 1 cm, 82.0 ± 8 kg and 24.9 ± 2 kg m–2, respectively, participated in this study. All subjects had a normal medical history, and physical examination revealed no abnormalities. Eight subjects exercised, and seven control individuals rested to control for an effect of repeated muscle biopsies. There was no difference between the two groups with regards to age, weight, height, BMI or maximal oxygen uptake (
).
Ethics. Before the expeimental procedures, the subjects were given both oral and written information about the experimental procedures before providing their written informed consent. All studies were approved by the Copenhagen and Frederiksberg Ethics Committee, Denmark, and were performed in accordance with the Declaration of Helsinki.
Experimental procedures.
Cycle ergometer exercise was chosen as the mode of exercise in this study because this type of exercise is mainly concentric and induces minimal muscle damage and subsequent inflammation. The subjects performed two incremental maximal exercise tests to determine 
on a cycle ergometer (Monark 839E, Monark Ltd, Varberg, Sweden). The first one, a familiarization trial, was performed 5 days before the first experimental day; the second test was performed 2 days after the experimental day. On the experimental day, subjects arrived at 07.00 h, after an overnight fast including all kinds of beverages. The subjects rested for approximately 10 min in the supine position, after which a venous catheter was placed in an antecubital vein. Subsequently, the subjects performed 3 h of cycling at approximately 60%
, followed by 6 h of recovery. Muscle biopsies were obtained from the vastus lateralis prior to the exercise (0 h), immediately after exercise (3 h), and at 4.5, 6, 9 and 24 h, using the percutaneous needle biopsy technique with suction. To acquire the 24 h samples, the subjects reported to the laboratory the following day after an overnight fast. Control subjects rested in the laboratory for 9 h, reported to the laboratory the day after in a fasted state, and had biopsy samples taken at the same time points as during the exercise trial.
Biopsies were obtained by anaesthetizing the skin and the muscle fascia using lignocaine (20 mg ml–1; SAD, Copenhagen, Denmark). A 5–7 mm incision was made, and the Bergström needle introduced into the muscle tissue, suction applied and three to five cuts were made. Biopsies were obtained from both quadriceps and individual biopsies were obtained with a distance of at least 5 cm. The biopsy was divided into two parts. Approximately 50 mg of the biopsy was used for RNA isolation. If present, superficial blood was quickly removed, and the biopsy was frozen in liquid nitrogen. The other part of the biopsy was prepared for histochemical analysis by mounting a small muscle piece in Tissue-Tek (Sakura Finetek, Zoeterwoude, The Netherlands) and then frozen in 2-methyl-butane (Acros Organics, Geel, Belgium) precooled in liquid nitrogen. Both samples were stored at –80°C until analysed.
The design was identical to the exercise protocol used in a former study (Akerstrom et al. 2005), but different subjects participated in the former and the present study.
Isolation of RNA and reverse transcription
Total RNA was isolated from skeletal muscle with TriZol (Life Technology) as described by the manufacturer. The RNA concentration was determined spectrophotometrically, and 2 µg of RNA was reversed transcribed in a 100 µl reaction according to the manufacturer's instructions using random hexamer primers (TaqmanTM reverse transcription reagents, Applied Biosystems, Naerum, Denmark). The reactions were run in a Perkin-Elmer GeneAmp PCR system 9700 (Applied Biosystems) with conditions: 25°C for 10 min, 48°C for 30 min, and 95°C for 5 min.
Real-time polymerase chain reaction (PCR) analysis
Real-time PCR was performed on an ABI PRISM 7900 sequence detector (PE Biosystems). Each assay included (in triplicate): a cDNA standard curve of five serial dilution points (ranging from 1 to 0.01), a no-template control, a no-reverse transcriptase control, and 150 ng (35 ng for glyceraldehyde-3 phosphate dehydrogenase (GAPDH)) of each sample of cDNA. The amplification mixture was made from 17.5 µl 2 x TaqMan Universal MasterMix, 1.75 µl of 20 x TaqMan probe, and primer assay reagents, 7.5 µl of the cDNA preparation, and 8.25 µl water to give a final volume of 35 µl. The primers and probes for CXCR2 (code, Hs00174304_m1) and GAPDH (code, Hs99999905_m1) were predeveloped TaqMan probes, and primer sets were from Applied Biosystems (AB). All assay reagents were from AB. The amplification mixtures were amplified according to standard conditions (50°C 2 min, 95°C 10 min followed by 50 cycles of 95°C 15 sec, 60°C 1 min). The relative concentrations of CXCR2 and the endogenous control, GAPDH, were determined by plotting the threshold cycle (Ct) versus the log of the serial dilution points. GAPDH levels were not influenced by the exercise protocol and have recently been validated for this type of study (Mahoney et al. 2004; Lundby et al. 2005). The relative expression of CXCR2 was subsequently determined after normalization to GAPDH. For CXCR2, a slope of –3.31 and a correlation coefficient (r) value of 0.99 were obtained. The corresponding GAPDH values were –3.50 for slope and 0.99 for the r2 value. The y-intercept on the standard curves generated represents the cycle threshold value for 150 ng of sample CXCR2, which amounted to 30.5. The threshold value for 35 ng of GAPDH was 17.3.
Protein expression
Tissue processing. Muscle biopsies were sectioned in 6 µm consecutive sections on a Microm cryostat, and sections were immediately collected on glass slides, in order to be stained by immunohistochemistry.
Sections were pre-incubated in 0.5% H2O2 to quench endogenous peroxidase and afterwards incubated in 10% goat serum to block unspecific background staining.
Immunohistochemistry. The sections stained by immunohistochemistry were always processed simultaneously and under the same laboratory conditions. Sections were incubated overnight at 4°C with primary monoclonal mouse antihuman CXCR2/IL-8 receptor B (CXCR2) antibodies diluted 1:50 (clone 48311, code no. MAB331, RD Systems, Abingdon, UK). The primary antibodies were detected using biotinylated goat antimouse IgG diluted 1:200 (code 8774, Sigma-Aldrich, USA) for 30 min at room temperature followed by streptavidin–biotin–peroxidase complex (StreptABComplex/HRP, code K377, Glostrup, Denmark) prepared at the manufacturer's recommended dilutions for 30 min at room temperature. Afterwards, sections were incubated with biotinylated tyramide and streptavidin–peroxidase complex (code NEL700A, Perkin Elmer, Wellesley, MA, USA) prepared according to the manufacturer's recommendations. The immunoreaction was visualized using 0.015% H2O2 in 3,3-diaminobenzidine-tetrahydrochloride (DAB)/TBS for 10 min at room temperature. In order to evaluate the extent of non-specific binding in the immunohistochemical analysis, control sections were incubated in the absence of primary antibody or in the blocking serum. To exclude staining due to endogenous biotin, we pretreated sections sequentially with 0.01–0.1% avidin (code A9390, Sigma-Aldrich, USA) followed by 0.001–0.01% biotin (code B4501, Sigma-Aldrich, USA), each step lasting 20 min at room temperature, before the immunohistochemistry was performed. Comparing our immunohistochemical stainings with and without specific biotin blocking showed that in the used tissue, muscular endogenous biotin is unlikely to induce false positive immunostainings by binding to the used streptavidin. For the simultaneous examination and recording of the stainings, a Zeiss Axioplan 2 light microscope was used.
Statistics
All data were normally distributed after log transformation. Data are presented as geometric means ± S.E.M. A two-way repeated-measures ANOVA was used to detect changes over time or between groups. Post hoc analyses (Bonferroni adjusted t test) were performed to identify specific differences across time or between groups. Differences were considered significant at P < 0.05. Statistical calculations were performed using SYSTAT 8.0 software (Richmond, CA, USA).
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Vascular endothelial cells are the major source of CD105. Other cell types, including vascular smooth muscle cells, fibroblasts, macrophages, leukaemic cells of pre-B and myelomonocytic origin, express CD105 to a lesser extent. In skeletal muscle, however, expression of CD105 is most likely to reflect endothelial cells (Duff et al. 2003). Assessment of microvessel density with panendothelial markers, namely CD34, CD31 and von Willebrand factor, may not be accurate, since factor VIII stains large vessels with high sensitivity and capillaries with variable and focal staining (Akagi et al. 2002). It is also not specific for blood vessels, since it can stain lymphatics (Guidi et al. 1994). Transmembrane glucoprotein CD31 (platelet endothelial cell adhesion molecule) is found on endothelial cells and many haematopoietic cells (Miettinen et al. 1994). Although it is a good marker for endothelial cells, it also stains blood vessels. Also, the reliability of CD31 staining has been inconsistent between laboratories (Smith-McCune & Weidner, 1994). Therefore, we determined to evaluate microvessel quantification using the CD105, a marker that is preferentially expressed only in angiogenic vessels. We found that the exercise-induced CXCR2 protein is localized primarily to the microvascular endothelial cells, as judged by CD105. Interestingly, we found that the protein expression of CD105 appeared to be upregulated by exercise. The possible regulation of TGF-ß and its receptor was not the focus of this work. Previous studies have found only a modest effect of exercise on TGF-ß expression in skeletal muscle (Smith-McCune & Weidner, 1994; Breen et al. 1996) and neither room air training nor chronic hypoxic training appeared to alter TGF-ß mRNA levels significantly (Olfert et al. 2001). In the light of the small gene responses to exercise and the fact that hypoxic training abolished the TGF-ß mRNA response to exercise yet increased muscle capillarity, the importance of the TGF-ß system as an angiogenic regulator in response to or after exercise training is questionable. However, the unexpected finding in the present study that the TGF-ß receptor CD105 is regulated by exercise sheds new light on the TGF-ß system in exercise-induced angiogenesis.
The present study aimed to focus on the IL-8 receptor, since it was recently shown that acute exercise induces an increase in IL-8 protein expression within skeletal muscle fibres (Akerstrom et al. 2005). Interleukin-8 was released from the working muscle; however, no increase in the systemic plasma concentration of IL-8 was observed, suggesting that muscle-derived IL-8 may act locally. Neither IL-8 mRNA in skeletal muscle nor IL-8 arteriovenous differences across an exercising limb were evaluated in the present study. The time course of the CXCR2 mRNA response in the present study is, however, similar to the IL-8 mRNA response reported by Akerstrom et al. (2005) using a similar exercise protocol. Although speculative, an increase in CXCR2 expression with exercise lends some support to the hypothesis that muscle-derived IL-8 produced in response to an acute bout of exercise may act locally to stimulate angiogenesis through CXCR2 receptor signalling.
Exercise generates a powerful angiogenic stimulus within the active muscle, which leads to an increase in capillarity with training (Andersen & Henriksson, 1977; Hudlicka et al. 1992). Angiogenesis in skeletal muscle in response to exercise has been ascribed to increases in blood flow and accompanying capillary shear stress and/or wall tension, and to the contraction itself (Prior et al. 2004). However, little is known with regard to the regulation of exercise-induced angiogenesis. The most studied angiogenic factor involved in exercise-mediated angiogenesis is vascular endothelial growth factor (VEGF). Muscle contractions induce an increase in human VEGF mRNA in muscle tissue (Gustafsson et al. 1999; Richardson et al. 1999; Jensen et al. 2004). The increase is greatest (two- to eightfold) shortly after the exercise bout (2–4 h) and declines with time thereafter, returning to normal values within 24 h (Jensen et al. 2004). Moreover, the mRNA levels of the VEGF receptors VEGF1 and VEGF2 are also increased by exercise (Gavin et al. 2000; Gavin & Wagner, 2002; Lloyd et al. 2003). The VEGF gene contains an upstream regulatory sequence that increases VEGF mRNA production when bound by the hypoxia-inducible factor (HIF-1; Forsythe et al. 1996). A recent study reported that IL-8 was sufficient to sustain angiogenesis in vivo in HIF-1-deficient colon cancer cells, indicating that VEGF and IL-8 represent different angiogenic pathways (Mizukami et al. 2005). Interleukin-8 induction can be mediated via activation of NF-
B (Mizukami et al. 2005). NF-B signalling is induced by an acute bout of exercise in rat skeletal muscle (Ji et al. 2004, 2006). These findings suggest that, in addition to VEGF signalling, IL-8 signalling via the CXCR2 receptor may be an additional pathway of exercise-mediated angiogenesis in the skeletal muscle.
In summary, the IL-8 receptor CXCR2 is expressed in skeletal muscle biopsies, and the expression of CXCR2 mRNA and protein is transiently increased by exercise. Moreover, the CXCR2 protein is localized primarily to activated microvascular endothelium. Although speculative, these findings may support the hypothesis that muscle-derived IL-8 produced in response to exercise may act locally to stimulate angiogenesis by CXCR2 receptor signalling.
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