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Key Points Persistent systemic inflammation is a typical feature of inflammatory rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus Chronic inflammation predisposes to insulin resistance, dyslipidaemia, endothelial dysfunction, accelerated atherosclerosis and neurodegeneration, and thereby to a network of chronic diseases such as type 2 diabetes mellitus, cardiovascular disease and dementia Disease-specific symptoms and comorbidities might negatively affect mobility, physical activity and physical capacity of patients with inflammatory rheumatic diseases Physical inactivity can cause the accumulation of visceral fat, which, along with comorbidities, might further enhance the development of chronic diseases in a 'vicious cycle' of chronic inflammation During exercise, skeletal muscle produces myokines, which might mediate either a direct anti-inflammatory response with each bout of exercise or improvements in comorbidities, thereby indirectly having anti-inflammatory effects Exercise is no longer thought to aggravate inflammation; rather, physical activity is now advocated as an anti-inflammatory therapy for patients with rheumatic diseases Contrary to earlier beliefs, evidence now exists that exercise does not exacerbate systemic inflammatory diseases, such as rheumatoid arthritis. In this Review of exercise therapy for rheumatic diseases, the authors propose that, by interrupting a cycle of local inflammation, obesity, metabolic dysregulation and systemic inflammation, exercise is medicine. Persistent systemic inflammation, a typical feature of inflammatory rheumatic diseases, is associated with a high cardiovascular risk and predisposes to metabolic disorders and muscle wasting. These disorders can lead to disability and decreased physical activity, exacerbating inflammation and the development of a network of chronic diseases, thus establishing a 'vicious cycle' of chronic inflammation. During the past two decades, advances in research have shed light on the role of exercise as a therapy for rheumatic diseases. One of the most important of these advances is the discovery that skeletal muscle communicates with other organs by secreting proteins called myokines. Some myokines are thought to induce anti-inflammatory responses with each bout of exercise and mediate long-term exercise-induced improvements in cardiovascular risk factors, having an indirect anti-inflammatory effect. Therefore, contrary to fears that physical activity might aggravate inflammatory pathways, exercise is now believed to be a potential treatment for patients with rheumatic diseases. In this Review, we discuss how exercise disrupts the vicious cycle of chronic inflammation directly, after each bout of exercise, and indirectly, by improving comorbidities and cardiovascular risk factors. We also discuss the mechanisms by which some myokines have anti-inflammatory functions in inflammatory rheumatic diseases.

MiRNAs are potent intracellular posttranscriptional regulators and are also selectively secreted into the circulation in a cell-specific fashion. Global changes in miRNA expression in skeletal muscle in response to endurance exercise training have been reported. Therefore, our aim was to establish the miRNA signature in human plasma in response to acute exercise and chronic endurance training by utilizing a novel methodological approach. RNA was isolated from human plasma collected from young healthy men before and after an acute endurance exercise bout and following 12 weeks of endurance training. Global miRNA (742 miRNAs) measurements were performed as a screening to identify detectable miRNAs in plasma. Using customized qPCR panels we quantified the expression levels of miRNAs detected in the screening procedure (188 miRNAs). We demonstrate a dynamic regulation of circulating miRNA (ci-miRNA) levels following 0 hour (miR-106a, miR-221, miR-30b, miR-151-5p, let-7i, miR-146, miR-652 and miR-151-3p), 1 hour (miR-338-3p, miR-330-3p, miR-223, miR-139-5p and miR-143) and 3 hours (miR-1) after an acute exercise bout (P<0.00032). Where ci-miRNAs were all downregulated immediately after an acute exercise bout (0 hour) the 1 and 3 hour post exercise timepoints were followed by upregulations. In response to chronic training, we identified seven ci-miRNAs with decreased levels in plasma (miR-342-3p, let-7d, miR-766, miR-25, miR-148a, miR-185 and miR-21) and two miRNAs that were present at higher levels after the training period (miR-103 and miR-107) (P<0.00032). In conclusion, acute exercise and chronic endurance training, likely through specific mechanisms unique to each stimulus, robustly modify the miRNA signature of human plasma.

Chronic inflammation is involved in the pathogenesis of insulin resistance, atherosclerosis, neurodegeneration, and tumour growth. Regular exercise offers protection against type 2 diabetes, cardiovascular diseases, colon cancer, breast cancer, and dementia. Evidence suggests that the protective effect of exercise may to some extent be ascribed to the antiinflammatory effect of regular exercise. Here we suggest that exercise may exert its anti-inflammatory effect via a reduction in visceral fat mass and/or by induction of an anti-inflammatory environment with each bout of exercise. According to our theory, such effects may in part be mediated via muscle-derived peptides, so-called “myokines”. Contracting skeletal muscles release myokines with endocrine effects, mediating direct anti-inflammatory effects, and/or specific effects on visceral fat. Other myokines work locally within the muscle and exert their effects on signalling pathways involved in fat oxidation and glucose uptake. By mediating anti-inflammatory effects in the muscle itself, myokines may also counteract TNF-driven insulin resistance. In conclusion, exercise-induced myokines appear to be involved in mediating both systemic as well as local anti-inflammatory effects.

Recent evidence suggests that there is a link between metabolic diseases and bacterial populations in the gut. The aim of this study was to assess the differences between the composition of the intestinal microbiota in humans with type 2 diabetes and non-diabetic persons as control. The study included 36 male adults with a broad range of age and body-mass indices (BMIs), among which 18 subjects were diagnosed with diabetes type 2. The fecal bacterial composition was investigated by real-time quantitative PCR (qPCR) and in a subgroup of subjects (N = 20) by tag-encoded amplicon pyrosequencing of the V4 region of the 16S rRNA gene. The proportions of phylum Firmicutes and class Clostridia were significantly reduced in the diabetic group compared to the control group (P = 0.03). Furthermore, the ratios of Bacteroidetes to Firmicutes as well as the ratios of Bacteroides-Prevotella group to C. coccoides-E. rectale group correlated positively and significantly with plasma glucose concentration (P = 0.04) but not with BMIs. Similarly, class Betaproteobacteria was highly enriched in diabetic compared to non-diabetic persons (P = 0.02) and positively correlated with plasma glucose (P = 0.04). The results of this study indicate that type 2 diabetes in humans is associated with compositional changes in intestinal microbiota. The level of glucose tolerance should be considered when linking microbiota with metabolic diseases such as obesity and developing strategies to control metabolic diseases by modifying the gut microbiota.

Tumor Necrosis Factor-α Induces Skeletal Muscle Insulin Resistance in Healthy Human Subjects via Inhibition of Akt Substrate 160 Phosphorylation Peter Plomgaard 1 , Karim Bouzakri 2 , Rikke Krogh-Madsen 1 , Bettina Mittendorfer 3 , Juleen R. Zierath 2 and Bente K. Pedersen 1 1 Department of Infectious Diseases and the Copenhagen Muscle Research Centre, The Centre of Inflammation and Metabolism, Rigshospitalet University of Copenhagen, Faculty of Health Sciences, Copenhagen, Denmark 2 Department of Surgical Sciences, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden 3 Washington University, School of Medicine, St. Louis, Missouri Address correspondence and reprint requests to Bente Klarlund Pedersen, Rigshopitalet 7641, Blegdamsvej 9, DK-2200 Copenhagen N, Denmark. E-mail: bkp{at}rh.dk . Correspondencereprint requests may also be sent to Juleen R. Zierath, Karolinska Institutet, Department of Surgical Sciences, Section of Integrative Physiology, von Eulers väg 4, 4th floor S-171 77 Stockholm, Sweden. E-mail: juleen.zierath{at}fyfa.ki.se Abstract Most lifestyle-related chronic diseases are characterized by low-grade systemic inflammation and insulin resistance. Excessive tumor necrosis factor-α (TNF-α) concentrations have been implicated in the development of insulin resistance, but direct evidence in humans is lacking. Here, we demonstrate that TNF-α infusion in healthy humans induces insulin resistance in skeletal muscle, without effect on endogenous glucose production, as estimated by a combined euglycemic insulin clamp and stable isotope tracer method. TNF-α directly impairs glucose uptake and metabolism by altering insulin signal transduction. TNF-α infusion increases phosphorylation of p70 S6 kinase, extracellular signal–regulated kinase-1/2, and c-Jun NH 2 -terminal kinase, concomitant with increased serine and reduced tyrosine phosphorylation of insulin receptor substrate-1. These signaling effects are associated with impaired phosphorylation of Akt substrate 160, the most proximal step identified in the canonical insulin signaling cascade regulating GLUT4 translocation and glucose uptake. Thus, excessive concentrations of TNF-α negatively regulate insulin signaling and whole-body glucose uptake in humans. Our results provide a molecular link between low-grade systemic inflammation and the metabolic syndrome. AS160, Akt substrate 160 ERK, extracellular signal–regulated kinase IL, interleukin IRS, insulin receptor substrate JNK, c-Jun NH2-terminal kinase S6K, p70 S6 kinase TNF-α, tumor necrosis factor-α Footnotes P.P. and K.B. contributed equally to this work. Accepted June 23, 2005. Received April 5, 2005. DIABETES

Hypoferremia is a common response to systemic infections or generalized inflammatory disorders. In mouse models, the development of hypoferremia during inflammation requires hepcidin, an iron regulatory peptide hormone produced in the liver, but the inflammatory signals that regulate hepcidin are largely unknown. Our studies in human liver cell cultures, mice, and human volunteers indicate that IL-6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL-6-hepcidin axis is responsible for the hypoferremia of inflammation.

Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Activated Protein Kinase Andrew L. Carey 1 2 , Gregory R. Steinberg 2 , S. Lance Macaulay 3 , Walter G. Thomas 4 , Anna G. Holmes 1 , Georg Ramm 5 , Oja Prelovsek 1 , Cordula Hohnen-Behrens 5 , Matthew J. Watt 1 2 , David E. James 5 , Bruce E. Kemp 2 3 , Bente K. Pedersen 6 and Mark A. Febbraio 1 1 Cellular and Molecular Metabolism Laboratory, School of Medical Sciences, Royal Melbourne Institute of Technology (RMIT) University, Bundoora, Victoria, Australia 2 St. Vincent’s Institute and Department of Medicine, The University of Melbourne, Fitzroy, Victoria, Australia 3 Commonwealth Scientific and Industrial Research Organization Molecular and Health Technologies, Parkville, Victoria, Australia 4 Molecular Endocrinology Laboratory, Baker Heart Research Institute, Melbourne, Australia 5 Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia 6 The Centre for Inflammation and Metabolism, Department of Infectious Diseases and The Copenhagen Muscle Research Centre, Rigshospitalet University of Copenhagen, Faculty of Health Sciences, Copenhagen, Denmark Address correspondence and reprint requests to Mark A. Febbraio, PhD, Baker Heart Research Institute, P.O. Box 6492 St. Kilda Rd., Central Vic 8008, Australia. E-mail: mark.febbraio{at}baker.edu.au Abstract Although interleukin-6 (IL-6) has been associated with insulin resistance, little is known regarding the effects of IL-6 on insulin sensitivity in humans in vivo. Here, we show that IL-6 infusion increases glucose disposal without affecting the complete suppression of endogenous glucose production during a hyperinsulinemic-euglycemic clamp in healthy humans. Because skeletal muscle accounts for most of the insulin-stimulated glucose disposal in vivo, we examined the mechanism(s) by which IL-6 may affect muscle metabolism using L6 myotubes. IL-6 treatment increased fatty acid oxidation, basal and insulin-stimulated glucose uptake, and translocation of GLUT4 to the plasma membrane. Furthermore, IL-6 rapidly and markedly increased AMP-activated protein kinase (AMPK). To determine whether the activation of AMPK mediated cellular metabolic events, we conducted experiments using L6 myotubes infected with dominant-negative AMPK α-subunit. The effects described above were abrogated in AMPK dominant-negative–infected cells. Our results demonstrate that acute IL-6 treatment enhances insulin-stimulated glucose disposal in humans in vivo, while the effects of IL-6 on glucose and fatty acid metabolism in vitro appear to be mediated by AMPK. ACC, acetyl-CoA carboxylase AMPK, AMP-activated protein kinase DG, deoxyglucose EGP, endogenous glucose production FFA, free fatty acid GIR, glucose infusion rate IL-6, interleukin-6 IRS, insulin receptor substrate PI3-K, phosphatidylinositol 3-kinase rhIL-6, recombinant human IL-6 rmIL-6, recombinant mouse IL-6 SOCS, suppressor of cytokine signaling TNF-α, tumor necrosis factor-α Footnotes A.L.C. and G.R.S. contributed equally to this study. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted July 19, 2006. Received October 28, 2005. DIABETES

Myostatin is a secreted growth factor expressed in skeletal muscle tissue, which negatively regulates skeletal muscle mass. Recent animal studies suggest a role for myostatin in insulin resistance. We evaluated the possible metabolic role of myostatin in patients with type 2 diabetes and healthy controls. 76 patients with type 2 diabetes and 92 control subjects were included in the study. They were matched for age, gender and BMI. Plasma samples and biopsies from the vastus lateralis muscle were obtained to assess plasma myostatin and expression of myostatin in skeletal muscle. Patients with type 2 diabetes had higher fasting glucose (8.9 versus 5.1 mmol/L, P<0.001), plasma insulin (68.2 versus 47.2 pmol/L, P<0.002) and HOMA2-IR (1.6 versus 0.9, P<0.0001) when compared to controls. Patients with type 2 diabetes had 1.4 (P<0.01) higher levels of muscle myostatin mRNA content than the control subjects. Plasma myostatin concentrations did not differ between patients with type 2 diabetes and controls. In healthy controls, muscle myostatin mRNA correlated with HOMA2-IR (r = 0.30, P<0.01), plasma IL-6 (r = 0.34, P<0.05) and VO2 max (r = -0.26, P<0.05), however, no correlations were observed in patients with type 2 diabetes. This study supports the idea that myostatin may have a negative effect on metabolism. However, the metabolic effect of myostatin appears to be overruled by other factors in patients with type 2 diabetes.

Epidemiological data suggest that exercise training protects from cancer independent of BMI. Here, we aimed to elucidate mechanisms involved in voluntary wheel running-dependent control of tumor growth across chow and high-fat diets. Access to running wheels decreased tumor growth in B16F10 tumor-bearing on chow (− 50%) or high-fat diets (− 75%, p  < 0.001), however, tumor growth was augmented in high-fat fed mice (+ 53%, p  < 0.001). Tumor growth correlated with serum glucose ( p  < 0.01), leptin ( p  < 0.01), and ghrelin levels ( p  < 0.01), but not with serum insulin levels. Voluntary wheel running increased immune recognition of tumors as determined by microarray analysis and gene expression analysis of markers of macrophages, NK and T cells, but the induction of markers of macrophages and NK cells was attenuated with high-fat feeding. Moreover, we found that the regulator of innate immunity, ZBP1, was induced by wheel running, attenuated by high-fat feeding and associated with innate immune recognition in the B16F10 tumors. We observed no effects of ZBP1 on cell cycle arrest, or exercise-regulated necrosis in the tumors of running mice. Taken together, our data support epidemiological findings showing that exercise suppresses tumor growth independent of BMI, however, our data suggest that high-fat feeding attenuates exercise-mediated immune recognition of tumors.

Skeletal muscle has the capacity to produce, express and release several hundred secreted peptides, so-called myokines. This finding provides a conceptual basis and a new paradigm for understanding the role of skeletal muscle in organ crosstalk, including muscle–liver and muscle–adipose tissue crosstalk. This Review highlights the clinical role of myokines in mediating the multiple health benefits of exercise. During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases. Key Points Myokines are cytokines or other peptides that are produced, expressed and released by muscle fibres Myokines may exert autocrine, paracrine or endocrine effects Myokines may balance and counteract the effects of adipokines The muscle–cell secretome consists of several hundred secreted products Identified myokines include myostatin, LIF, IL-6, IL-7, BDNF, IGF-1, FGF-2, FSTL-1 and irisin Myokines may mediate protective effects of muscular exercise, with regard to diseases associated with a physically inactive lifestyle