Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 15, 2026.

Muscle–Organ Crosstalk: The Emerging Roles of Myokines

Mai Charlotte Krogh Severinsen, Bente Klarlund Pedersen

Endocrine Reviews · 2020 · Review · CC BY

doi:10.1210/endrev/bnaa016

Abstract

Physical activity decreases the risk of a network of diseases, and exercise may be prescribed as medicine for lifestyle-related disorders such as type 2 diabetes, dementia, cardiovascular diseases, and cancer. During the past couple of decades, it has been apparent that skeletal muscle works as an endocrine organ, which can produce and secrete hundreds of myokines that exert their effects in either autocrine, paracrine, or endocrine manners. Recent advances show that skeletal muscle produces myokines in response to exercise, which allow for crosstalk between the muscle and other organs, including brain, adipose tissue, bone, liver, gut, pancreas, vascular bed, and skin, as well as communication within the muscle itself. Although only few myokines have been allocated to a specific function in humans, it has been identified that the biological roles of myokines include effects on, for example, cognition, lipid and glucose metabolism, browning of white fat, bone formation, endothelial cell function, hypertrophy, skin structure, and tumor growth. This suggests that myokines may be useful biomarkers for monitoring exercise prescription for people with, for example, cancer, diabetes, or neurodegenerative diseases.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 15, 2026. Paragraph numbers are ours, so an answer can point at one.

Myokines are defined as cytokines and other peptides that are produced, expressed and released by muscle fibers and exert either autocrine, paracrine, or endocrine effects

Myokines mediate communication between muscle and other organs, including brain, adipose tissue, bone, liver, gut, pancreas, vascular bed, and skin, as well as within the muscle itself

Myokines exert their effects on, for example, cognition, lipid and glucose metabolism, browning of white fat, bone formation, endothelial cell function, hypertrophy, skin structure, and tumor growth

The myokine IL-6 mediates the exercise-associated anti-inflammatory effects both acutely with each bout of exercise and as a consequence of training adaptation, including reduction in abdominal adiposity.

The identification of new myokines and their specific roles may lead to novel therapeutic targets

Myokines can be useful biomarkers for monitoring the type and amount of exercise that are required for the prescription of exercise for people with, for example, cancer, diabetes, or neurodegenerative diseases

Within the society of human integrative physiology, the awareness of an exercise factor that is able to mediate exercise-induced changes in other organs such as liver and adipose tissue dates back more than 50 years. It was clear that signaling pathways from exercising skeletal muscle to other organs were not solely mediated via the nervous system, since electrical stimulation of paralyzed muscles in patients with no efferent or afferent nerve impulses induced the same types of physiological changes as were found in healthy human beings. Thus, it was obvious that 1 or several humoral factors had to be released from contracting muscles to the blood.

Before such factors were identified, they were referred to as the “work factor” or the “exercise factor”. Our finding in 2000 that skeletal muscle produced and released interleukin-6 (IL-6) into the circulation as well as research during the subsequent years, demonstrating that IL-6 has multiple metabolic effects in other parts of the body, identified IL-6 as an exercise factor and skeletal muscle as a secretory organ with endocrine functions.

Given the multiple physiological, metabolic, and immunological effects of exercise, it was obvious that more than 1 exercise factor was likely to be found. In 2003, we introduced the term “myokines” and suggested that “cytokines and other peptides that are produced, expressed and released by muscle fibers and exert either autocrine, paracrine or endocrine effects should be classified as myokines”.

Following the identification of muscle-derived IL-6, it soon became clear that muscles were able to secrete hundreds of peptides. Although the biological function has been described for only 5% of all known myokines, the identification of the myokinome has provided a new paradigm and a conceptual basis for understanding by which mechanisms muscles communicate with other organs. It has been proposed that the total sum of all exercise-induced factors (such as peptides and nucleic acids) released from muscle and other organs into the blood should be named “exerkines”. Exerkines may be released within extracellular vesicles known as exosomes, which may contain nucleic acids, peptides, messenger ribonucleic acid (mRNA), microRNA and mitochondrial deoxyribonucleic acid. Although there is an overlap between myokines and exerkines, the present review focuses on myokines.

The role of myokines has previously been reviewed, identifying more than 650 myokines. Some myokines are responsible for mediating energy supply in relation to acute bouts of exercise. Myokines are also involved in muscle proliferation, differentiation, and regeneration independent of exercise. During exercise, myokines signal within the muscle and mediate muscle–organ crosstalk to the brain, adipose tissue, bone, liver, gut, pancreas, vascular bed, and skin. In addition, myokines with anticancer effects have been recognized. The aim of the present review is to provide an update of recent advances within the myokine field.

Myogenesis

Some myokines exert their effect within skeletal muscle itself and are involved in the regulation of muscle mass (Fig. 1).

Myostatin was the first identified muscle-derived factor that fulfills the myokine criteria as outlined above. Myostatin is a member of the transforming growth factor β (TGF-β) superfamily and negatively regulates myogenesis in an autocrine manner. Massive muscle hypertrophy is seen in myostatin knockout mice, cattle, sheep, and dogs that demonstrate an increase in fiber cross-sectional area and in fiber number.

Decorin has been identified as a myokine that is regulated by exercise and acts as an antagonist to myostatin. Circulating levels of decorin are increased in response to exercise in humans, whereas exercise training reduces the levels of myostatin within muscles and blood.

Although the myokine IL-6 is mostly recognized for its regulatory effects in lipid and glucose metabolism, IL-6 also plays important roles in myogenesis. Muñoz-Cánoves and her team identified IL-6 as an anabolic factor in preclinical models. Genetic loss of IL-6 impaired muscle hypertrophy in vivo, whereas myotube-produced IL-6 stimulated muscle cell proliferation in a paracrine fashion.

Leukemia inhibitory factor (LIF) is a member of the IL‑6 cytokine superfamily and has multiple biological functions. LIF protein has been shown to be secreted from human cultured myotubes; when electrically stimulated LIF stimulates satellite cell proliferation. It has further been shown that both IL-6 and LIF activate myotube mTORC1 signaling in a time- and dose-dependent fashion.

A number of other myokines, including IL‑15 and IL-7 have further been demonstrated to possess anabolic features in rodent models.

Metabolic actions

While IL-6 is characterized as a myokine with endocrine effects, it also works in a paracrine manner exerting metabolic effects within the muscle itself.

Physical inactivity is associated with high circulating basal levels of IL-6 in humans. Moreover, the acute exercise-induced rise in systemic levels of IL-6 and muscular IL-6 mRNA are diminished by training in humans. In contrast, the muscular expression of the IL-6 receptor (IL-6R) is elevated in trained human muscle, suggesting that muscular sensitivity to IL-6 is increased by training adaptation. IL-6 signaling within the muscle can affect both glucose uptake and fat oxidation.

It is well documented that IL-6 increases both basal glucose uptake and glucose transporter GLUT4 translocation. In addition, IL-6 increases insulin-stimulated glucose uptake in vitro and in healthy humans in vivo. Thus, when recombinant human IL-6 (rhIL-6) was infused into healthy humans together with a hyperinsulinemic, euglycemic clamp, it improved peripheral insulin-stimulated glucose uptake. The effects of IL-6 on glucose uptake in vitro was shown to be mediated by activation of adenosine 5′-monophosphate-activated protein kinase (AMPK). Several other studies have described that IL-6 can increase intramyocellular or whole body fatty acid oxidation via AMPK activation.

Brain-derived neurotrophic factor (BDNF) is also expressed in human skeletal muscles, but BDNF is not released into the circulation and does not work in an endocrine way. In contrast, BDNF is identified as a myokine capable of enhancing AMPK activation and hence lipid oxidation in an autocrine or paracrine manner.

Musclin has been identified as an exercise-induced factor promoting skeletal muscle mitochondrial biogenesis in mice. Recent evidence shows that musclin abolishes muscle atrophy related with cancer in mice.

Muscle–Brain Crosstalk

Evidence is accumulating that physical exercise has positive health effects on cognitive function and brain health. Physical activity and exercise training decrease the risk of dementia and appear to play a role in the treatment of this disease. In general, it is found that physical activity decreases the rate of cognitive decline in healthy people and in people with neurodegenerative disorders across the life span. Moreover, physical exercise has a positive impact on stress, anxiety, and depression. Other studies have shown that an active lifestyle is associated with learning and memory, executive functions, language and reaction time, academic achievement in children, and intelligence in adolescents. Physical activity has also beneficial effects on appetite, sleep, and mood.

Exercise has been shown to influence the hippocampus more than any other part of the brain. Studies in rodents and humans have shown that exercise increases hippocampus volume and the blood flow to this part of the brain. In particular, exercise has been shown to influence neurogenesis in the dentate gyrus and to increase synapse plasticity.

The finding that muscle contraction is sensed by the brain suggests that peripheral factors induced by exercise may be involved in direct crosstalk between working muscle and brain function (Fig. 2).

Cognition, hippocampal neurogenesis, and learning

Recent findings suggest that a muscle–brain endocrine loop exists, which at least in part may be mediated by myokine signaling. Other possible mediators include various metabolites, noncoding RNAs, hormonal responses, and muscular enzymes with impact on circulating compounds. BDNF appears to play a dominant role in mediating the effects of exercise on hippocampus. Rodent studies demonstrate increased BDNF mRNA and BDNF protein within the hippocampus in response to wheel running for 1-8 weeks. Furthermore, BDNF has been shown to be mechanistically linked to exercise-induced improvement in cognitive functions, such as memory and learning.

Studies in humans show that BDNF is released from the brain during a bout of bicycle exercise, and aerobic exercise training for 3 months increases the volume of the hippocampus in healthy individuals by 12% and by 16% in patients with schizophrenia. BDNF is a growth factor for the hippocampus and involved in, for example, cell survival and learning. The finding that BDNF is also expressed in human skeletal muscle during exercise is interesting; however, muscle-derived BDNF has not been shown to be released from muscle into the blood stream, thereby mediating a direct muscle–brain interaction.

A couple of interesting studies propose that the myokines cathepsin-B and irisin may pass the blood–brain barrier and provoke an increase in BDNF. Moon et al. recently identified a novel myokine, cathepsin B (CTSB) and demonstrated in a series of elegant studies that exercise leads to elevated systemic levels of CTSB, which promote expression of BDNF in the hippocampus and stimulate neurogenesis. Running led to an increased muscular expression of the CTSB gene in mice and an increase in CTSB in plasma from mice, rhesus monkeys, and in humans following treadmill running for 4 months. CTSB was furthermore shown to pass the blood–brain barrier in mice. Moon et al. also performed studies in CTSB knockout mice and showed that mice lacking CTSB were resistant to an effect of voluntary exercise as regards hippocampal growth and improved cognition. It is not known if the myokine CTSB mediates enhanced cognitive functions in humans in response to exercise training.

The PGC-1α-dependent myokine irisin, known for its browning effects, may also be involved in mediating effects of physical activity on the brain. When irisin is overexpressed in primary cortical neurons, it leads to an increase in BDNF expression, whereas RNAi-mediated knockdown of FNDC5 is followed by a reduction of BDNF. Moreover, systemic levels of irisin is elevated when irisin is delivered to the murine liver via adenoviral vectors, which leads to increased levels of BDNF in the hippocampus. It is controversial whether exercise raises plasma concentrations of irisin in humans, and whether irisin is involved in a muscle–brain endocrine loop.

Appetite

Elevated levels of IL-6 accompany, for example, obesity and type 2 diabetes, and IL-6 is often linked with the metabolic syndrome, not least in animal models. However, IL-6 has also been shown to affect metabolic actions beneficially. IL-6-deficient mice gain weight and develop whole-body insulin resistance. Other rodent studies show that IL-6 triggers proliferation of pancreatic alpha cells in the obese state and stimulates the production of glucagon-like peptide (GLP)-1 and hence insulin secretion. Studies in murine macrophages and hepatocytes show that IL-6 improves glucose homeostasis.

Human studies demonstrate that physiological levels of IL-6 have many positive effects, including an enhancement of both insulin-stimulated glucose uptake and lipolysis and fat oxidation. IL-6 also delays gastric emptying and thereby exerts effects on postprandial glucose control. Infusion of IL-6 to humans stimulates the production of IL-1ra and IL-10 and inhibits endotoxin-induced tumor necrosis factor (TNF) production, thereby inducing anti-inflammatory effects.

During muscle work, IL-6 is produced by human contracting skeletal muscle and released into the blood in a TNF-independent fashion. The release of IL-6 leads to an exponential rise in circulating concentrations of IL-6 in humans. Systemic IL-6 knockout mice accumulate adipose tissue, whereas central overexpression of IL-6 leads to a decrease in body weight, indicating that IL-6 is a player in body weight control. Another murine study demonstrated that lack of muscular IL-6 led to a decrease in body weight and food consumption in response to leptin.

A study showed that IL-6 improves glucose tolerance and suppresses feeding when it is applied centrally in mice, but not intraperitoneally at the same dose. However, a 4-fold higher IL-6 concentration injected peripherally significantly reduced food intake. This finding suggests that high systemic concentrations of IL-6 can pass the blood–brain barrier and exert central effects on appetite. Thus, it is likely that muscle-derived IL-6, elicited by exercise of long duration and high intensity, may inhibit appetite.

Muscle–Adipose Crosstalk

Myokines are involved in the regulation of lipid metabolism in relation to exercise and recent evidence suggests that some myokines may also have the capacity to induce browning of white adipose tissue (Fig. 3).

Lipolysis

The effect of exercise-induced IL-6 on fat metabolism is one of the most well supported findings. In vitro studies and studies in rodents show that IL-6 can enhance lipolysis and fat oxidation, via a mechanism that involves AMPK activation. In vivo studies show that rhIL-6 enhances lipolysis and fat oxidation in healthy young and elderly humans and IL-6 autoantibodies appear to be involved in the pathogenesis of a subset of type 2 diabetes.

Abdominal adiposity is associated with type 2 diabetes, cardiovascular disease, dementia, colon cancer, and breast cancer. Abdominal adiposity is also associated with all‐cause mortality, both in obese people and in people with a normal body weight. Epidemiological studies clearly show that an association exists between abdominal adiposity and low fitness as well as between abdominal adiposity and low-grade inflammation. Intervention studies show that physical inactivity promotes an increase in the amount of visceral adipose tissue, whereas exercise training diminishes visceral adipose tissue mass.

It was, however, not until recently that a mechanism underlying the link between exercise and abdominal fat was established. Abdominally obese humans were randomized to tocilizumab (IL-6 receptor antibody) or placebo during an intervention of 12 weeks with either aerobic exercise or no exercise. As expected, exercise training led to a reduction in visceral adipose tissue mass. However, this effect was abolished by IL-6 receptor blockade. Moreover, IL-6 receptor blockade abolished the exercise-induced loss of cardiac fat.

Browning

Brown fat expresses a set of proteins, such as uncoupling protein 1 (UCP1). The fact that white adipose tissue can shift into a brown-like phenotype, the discovery of brown fat in humans, and the potentially beneficial effects of these depots have stimulated a number of studies to explore whether lifestyle, such as exercise, can contribute to induce browning of white fat.

In 2012, irisin was reported as a myokine with the ability to brown white adipose tissue in mice. It was shown that muscular PGC1-α expression stimulates an increase in the expression of the membrane FNDC5 that is cleaved and secreted as irisin. Cell culture studies demonstrated that irisin stimulates UCP1 expression and other brown fat-like genes. However, while evidence exists that irisin is released from rodent muscle and has browning effects, it is debated whether exercise leads to an increase in plasma irisin levels in humans. The controversy is mainly based on the fact that previous studies have used commercial enzyme-linked immunosorbent assay kits for irisin, which seems to be unspecific.

A couple of other exercise-induced myokines with browning effects have been identified. In 2014, Spiegelman’s group identified meteorin-like (Metrnl), a circulating muscle-derived factor, that is induced in muscle after exercise. Metrnl stimulates the expression of genes associated with beige fat thermogenesis, it further stimulates energy expenditure and improves glucose tolerance. Yet, the role of Metrnl in humans remains to be identified.

A world of literature has proven that IL-6 is released from contracting human muscle cells into the circulation and that it contributes to the exponential increase in plasma IL-6 in relation to exercise, reviewed in,,. Studies suggest that IL-6 can induce browning of white adipose tissue. Daily intraperitoneal injections of IL-6 to mice for 1 week increased UCP1 mRNA in inguinal white adipose tissue.

A study by Kristóf et al. found that IL-6 was mainly produced by fully differentiated adipocytes. When the IL-6 receptor was blocked during differentiation, brown marker genes were downregulated, suggesting that beige adipocytes regulate IL-6 production to enhance browning in an autocrine manner. It remains to be shown that the physiological concentrations of IL-6, released during exercise, have browning effects.

There are a few other circulating factors during exercise, which have the potential to induce browning. β-Aminoisobutyric acid is a small molecule, a nonprotein beta-amino acid, not classified as a myokine, but secreted from myocytes. Moreover, β-aminoisobutyric acid has browning effects on human adipocytes. In addition, 2 hepatokines appear to play a role in exercise-induced browning of white adipose tissue. The Fibroblast growth factor 21 (FGF-21) and Follistatin are released from human liver during exercise and this release is controlled by the glucagon-to-insulin ratio. Evidence exists that both Follistatin and FGF-21 can induce browning of white adipose tissue cells.

The finding that circulating factors during exercise may induce browning of white adipose tissue has so far largely been restricted to rodents and has not been consistently demonstrated in humans.

Muscle–Bone Crosstalk

Muscle and bone are closely related during development growth, and muscle disuse and/or muscle atrophy result in osteoporosis. As pointed out by Guo et al., muscle mass, measured as lean body mass, can only explain up to 20% of the variety in bone mineral density and decreased mechanical loading, as seen with muscle atrophy alone, is not likely to fully explain the loss of bone mass. It is obvious that bone mass could also be regulated by muscle-derived biochemical factors such as myokines (Fig. 4).

Studies in mice show that inhibition of the myokine myostatin pathway leads to an increase in bone mass, whereas myostatin reduces osteoclast formation and bone destruction in a TNF-α transgenic mouse model of rheumatoid arthritis. Thus, whereas myostatin is a negative regulator of bone, it is a positive regulator of bone resorption.

Overexpression of IL-6 in IL-6 transgenic mice resulted in increased osteoclastogenesis. IL-6 appears to induce bone resorption through receptor activator of nuclear factor kappa-Β ligand (RANKL) -dependent enhanced osteoclastogenesis/osteoclast differentiation as well as via osteoblast-derived prostaglandin E2 (PGE2)-dependent osteoclast activation.

Given that trained people have low circulating basal levels of IL-6, whereas IL-6 increases with each bout of exercise, the interpretation of the findings above only makes sense if it is the chronic basal levels of IL-6 that modulate bone, rather than the acute peaks in IL-6 levels as also pointed out by Banfi.

Insulin-like growth factor 1 (IGF-1) has been shown to have a positive effect on bone formation. Muscle-derived IGF-1 can act on local osteoblasts that express the IGF-1 receptor and thereby promote bone formation.

Osteoglycin is a myokine that appears to inhibit myoblast migration during myogenesis. Other myokines have been shown to affect bone metabolism, either positively (IGF-I, FGF-2, IL-15), or negatively (eg, TGF-β).

Muscle–Liver Crosstalk

In order to maintain glucose homeostasis during exercise, glucose uptake in muscle is accompanied by increased glucose production from the liver. Mediators of endogenous glucose production include an increase in the portal venous glucagon-to-insulin ratio, epinephrine, and norepinephrine, but these factors cannot alone account for the rapid increase in glucose production (reviewed in, eg,. In 1961, Goldstein suggested that muscle cells might be able to produce a “humoral” component that could contribute to hepatic glucose production.

We infused rhIL-6 into resting human subjects and showed that acute administration of physiological concentrations of rhIL-6 did not influence whole-body glucose disposal, glucose uptake, or endogenous glucose production. However, in 2004, we published a study showing that during bicycle exercise IL-6 contributes to the increase in endogenous glucose production. Healthy young males underwent 2 hours of bicycle exercise on 3 separate occasions at (1) a relatively high intensity; (2) a low intensity, and (3) a low intensity + infusion of IL-6 to mimic the plasma levels of IL-6 observed during high-intensity exercise. The study showed the existence of direct muscle–liver crosstalk. Muscle-derived IL-6 plays a role in triggering glucose output from the liver during exercise in humans.

A murine study from 2018 showed that IL-6 treatment enhances AKT signaling and reduces gluconeogenic gene expression in livers from low and high fat fed mice, demonstrating that the beneficial effects of IL-6 on glucose and insulin homeostasis, in vivo, are maintained in obesity.

Muscle–Gut Crosstalk

A classic study by Ellingsgaard et al. elegantly showed that acute elevations in IL-6 stimulates GLP-1 secretion from both intestinal L‐cells and pancreatic β‐cells, leading to improved secretion of insulin. This finding implicates IL‐6 in a beneficial regulation of insulin secretion and suggests that IL‐6 is involved in an endocrine loop that may protect against impaired glucose homeostasis (Fig. 5).

A recent study from our group looked at the effects of IL-6 on postprandial glycemia and insulin secretion in humans and found that IL-6 delays the rate of gastric emptying, which is the most significant regulator of postprandial glucose. The study identifies a new role of human IL-6 being involved in gastric emptying and sparing insulin in a postprandial situation.

Muscle–β-Cell Crosstalk

It is well established that exercise can enhance insulin sensitivity, whereas it is less clear whether exercise can improve insulin secretion and whether a communication exists between insulin-resistant skeletal muscle and pancreatic β-cells.

It has previously been shown that excessive concentrations of TNF-α induce insulin resistance in humans in vivo. We used TNF-α to induce insulin resistance in human myotubes. Conditioned media from muscle cells incubate with and without TNF-α were added to human and rat primary β-cells. The study identified a link between skeletal muscle and β-cells that is influenced by the insulin resistant state of the muscle.

Studying primary muscle cell cultures established from triceps brachii, soleus, and quadriceps led to the identification of angiogenin and osteoprotegerin, which were shown to be triceps-specific myokines that could mediate anti-inflammatory actions and protect β-cell survival. These results indicate that type I and type II muscles impact insulin secretion differentially in type 2 diabetes via specific myokines secretion.

Whereas TNF-α may inhibit β‐cell function indirectly, IL‐1β has been identified as a direct key player in β‐cell damage, although IL-1β inhibition with canakinumab did not reduce the incidence of diabetes. It has clearly been shown that IL‐6 positively regulates β‐cell mass in vivo by stimulating β‐cell proliferation and preventing apoptosis induced by metabolic stress. Therefore, exercise‐induced increase in IL‐6 production may be involved in protecting pancreatic β‐cell mass and function.

Muscle–Vascular Bed Crosstalk

By stimulating the in vivo growth of functional type II muscle fibers, the Walsh group identified novel muscle-secreted factors. Follistatin-like 1 (FSTL1) was shown to be produced by both skeletal and cardiac muscle cells and is also termed a cardiokine.

FSTL1 has been shown to possess cardioprotective effects, promoting endothelial cell function and thereby revascularization in animal models of cardiac injury through a mechanism that includes nitric oxide synthase. Circulating levels of FSTL1 may work as a biomarker as high concentrations of FSTL1 are seen in patients with systolic and diastolic heart failure, and as FSTL1 levels exhibit prognostic significance in the acute coronary syndrome. Using a dog model, it was recently shown that FSTL1 can positively regulate myocardial substrate metabolism, in vivo.

Muscle–Skin Crosstalk

Aging is associated with numerous alterations, including changes of the skin. Tarnopolsky and colleagues demonstrated that endurance exercise improves age-associated skin changes in both mice and humans. They showed that exercise regulates muscular IL-15 expression via skeletal muscle AMPK. Elimination of muscle AMPK led to a weakening of skin structure, whereas IL-15 injections mimic some of the anti-aging effects of exercise on murine skin. The study supports the idea that exercise retards skin aging via a mechanism that involves muscle-derived IL-15.

Muscle–Immune Inflammation Crosstalk

During exercise, muscle works as an immunoregulatory organ with impact on leukocyte subset trafficking and inflammation (Fig. 6).

Lymphocyte and neutrophil trafficking

During exercise, lymphocytes and neutrophils are mobilized to the blood. Following long-duration exercise of high intensity, the concentration of lymphocytes falls below pre-exercise values whereas the neutrophil number continues to increase. The acute exercise effect on lymphocytes and neutrophils is mediated by adrenaline, but the post-exercise reduction in lymphocyte number and the continuous increase in neutrophil number are mediated by both adrenaline and cortisol.

There are some indications that the exercise-induced rise in cortisol is mediated by IL-6. The infusion of IL-6 to mimic the effects of exercise led to an increase in cortisol and, consequently, a decrease in the lymphocyte number accompanied by an increase in neutrophil number.

Two other studies payed some support to a possible link between IL-6, lymphocyte number and cortisol. Carbohydrate ingestion during exercise blunted the exercise-induced IL-6 response, the increase in lymphocyte number as well as the cortisol. Moreover, antioxidant supplementation totally inhibited the release of IL-6 from exercising human muscle as well as the exercise-induced increase in systemic levels of cortisol.

The anti-inflammatory effects of exercise

Physical inactivity is associated with low-grade chronic inflammation, not least when a physical inactive lifestyle is associated with obesity.

In humans, exercise training can induce anti-inflammatory effects both acutely with each bout of exercise and via long-term training adaptation including reduction in abdominal adiposity. The exercise-induced acute increase in IL‐6 stimulates an anti-inflammatory systemic environment. Thus, IL-6 promotes an increase in the production of the anti-inflammatory cytokines, IL‐1 receptor antagonist (IL‐1ra) and IL‐10. IL‐1ra inhibits IL‐1β signal transduction and IL‐10 inhibits synthesis of TNF‐α.

We infused a very low dose of Escherichia coli endotoxin to healthy subjects, who were randomized to either rest or exercise prior to the endotoxin administration. Exercise prior to endotoxin totally blunted the increase in circulating levels of TNF‐α that was observed during a resting situation.

Previous studies in cultured human monocytes have shown that IL‐6 prevents endotoxin-induced TNF‐α production. Moreover, it was shown that IL‐6‐deficient knockout mice have elevated levels of TNF‐α. It was therefore expected that an infusion of rhIL-6 prior to endotoxin administration would also blunt the TNF‐α response in humans and this was in fact what was found.

Together these data show that an acute bout of exercise induces anti‐inflammatory effects that may at least partially be mediated by IL‐6, not excluding other anti-inflammatory factors such as adrenaline and cortisol, as previously discussed.

A recent murine study suggested that IL-6 may induce either pro- or anti-inflammatory actions depending on cell source. Using a mouse model with conditional expression of the Il6 gene, it was found that IL6 derived from adipocytes increased, while IL6 derived from myeloid cells and muscle suppressed, macrophage infiltration of adipose tissue. The finding of opposite actions of IL-6, depending of the cell source, appeared to be due to a switch of IL6 signaling from a canonical mode (myeloid cells) to a noncanonical trans-signaling mode (adipocytes and muscle) which involved increased expression of the ADAM10/17 metalloprotease that enhances trans-signaling via the soluble IL6 receptor α.

Long-term anti-inflammatory effects are facilitated via exercise-training reduction in abdominal fat. In fact, an association has been established between physical inactivity and visceral fat in both rodents and humans. Accumulation of visceral fat, which is more inflamed than subcutaneous fat, leads to chronic systemic inflammation that predisposes to atherosclerosis, elevated blood lipids, insulin resistance, neurodegeneration, muscle waste, and anemia, factors that are likely to lead to decreased physical activity. Lack of exercise provokes accumulation of more visceral fat and thereby further enhances inflammation and hence a network of chronic diseases. Thereby, a vicious circle of chronic inflammation is established.

Exercise training will lead to a decrease in visceral and cardiac fat mass and hence a decrease in circulating inflammatory molecules via a mechanism that involves exercise-induced increase in IL-6, as described above.

Muscle–Cancer Crosstalk

Epidemiological studies suggest that physical activity in leisure time reduces the risk of at least 13 different cancer types. People who are physically active after a diagnosis of prostate cancer, colorectal cancer, and breast cancer have a higher survival rate than physically inactive people suffering from the same cancer types.

It is obvious, that many cancers are accompanied by systemic low-grade chronic inflammation and that such inflammation may drive tumor progression. Therefore, the anti-inflammatory effects of physical training may mediate some of the protective effects of exercise on cancer development.

Pernille Hojman and her team explored the effect of exercise on tumor growth in preclinical models. She first established a B16F10 melanoma model and randomized tumor-bearing mice to voluntary wheel running or control. Running mice demonstrated a marked reduction in tumor volume and incidence across 6 different tumor models. The effects of exercise on cancer growth were mediated via a direct regulation of natural killer cells by a mechanism that involved epinephrine-dependent mobilization of natural killer cells to the circulation and an IL-6-dependent redistribution to tumors. Blocking IL-6 signaling during exercise abolished the exercise-induced inhibition of tumor growth. The findings in mice indicate that IL-6 may have a role in mediating anti-cancer effects.

A few mechanistic studies have demonstrated a potential role of other myokines, including Oncostatin M, irisin, and SPARC in the suppression of breast and colon cancer growth.

Myokines and Other “Kines”: Adipokines, Hepatokines, and Batokines

The views on organ crosstalk in health and disease have changed over the past 30 years.

It all began with the work from the Spiegelman and Flier laboratories in 1987 that defined adipose tissue as an endocrine organ by the identification of a secretory protein, called adipsin. This was followed by a landmark finding by Friedman and his team, who identified leptin. Since then the list of adipokines have included, for example, adiponectin, resistin, and visfatin.

The identification of muscle as a secretory organ began with the finding of muscle-derived IL-6 in 2000 and the subsequent definition of myokines in 2003, and led via the work of many research groups later to the identification of hundreds of myokines. The present review identifies crosstalk between muscle and several other organs, including brain, adipose tissue, bone, liver, gut, pancreas, vascular bed, and skin. Moreover, several myokines signal within the muscle itself (Fig. 7).

Recently, a novel group of liver-derived exercise factors has been identified. Hepatokines include FGF-21, follistatin, angiopoietin-like protein 4, heat shock protein 72, and IGF binding protein, which are all released from the liver during or immediately after an exercise bout. These hepatokines increase in the circulation after muscle work and appear to be involved in mediating some of the metabolic effects of exercise.

The latest news regarding other “kines” started with the identification of classic brown adipose tissue in adult humans, which led to the batokine concept. Most recently, 101 proteins were exclusively quantified into brown and not white adipocyte tissue by proteomic-based identification.

However, among the “kines,” focus is still primarily on myokines and hepatokines when it comes to mediating exercise-induced communication between muscle and other organs. Lack of physical activity is associated with a large network of diseases, including type 2 diabetes, cardiovascular diseases, cancer, dementia, and osteoporosis, and it is likely that the detrimental effects of lack of exercise to some degree is mediated by a lack of myokine release and/or resistance to the effects of myokines. The identification of new myokines and their specific roles will likely lead to novel therapeutic targets for lifestyle-related diseases. However, the biological identification of several myokines has turned these molecules into useful biomarkers for monitoring the amount, intensity, and mode of exercise that is sufficient to induce specific physiological and metabolic responses for people with, for example, cancer, diabetes, or neurodegenerative diseases.

References 234

  1. 1.

    Kjaer M, Secher NH, Bangsbo J, et al. Hormonal and metabolic responses to electrically induced cycling during epidural anesthesia in humans. J Appl Physiol (1985). 1996;80(6):2156-2162.

    Not in our library10.1152/jappl.1996.80.6.2156

  2. 2.

    Mohr T, Andersen JL, Biering-Sørensen F, et al. Long-term adaptation to electrically induced cycle training in severe spinal cord injured individuals. Spinal Cord. 1997;35(1):1-16.

    Not in our library10.1038/sj.sc.3100343

  3. 3.

    Goldstein M. Humoral nature of hypoglycemia in muscular activity. Am J Physiol. 1961;200:67-70.

    Not in our library

  4. 4.

    Pedersen BK, Steensberg A, Fischer C, et al. Searching for the exercise factor: is IL-6 a candidate? J Muscle Res Cell Motil. 2003;24(2-3):113-119.

    Not in our library10.1023/a:1026070911202

  5. 5.

    Steensberg A, van Hall G, Osada T, Sacchetti M, Saltin B, Klarlund Pedersen B. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J Physiol. 2000;529(Pt 1):237-242.

    Not in our library10.1111/j.1469-7793.2000.00237.x

  6. 6.

    Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev. 2008;88(4):1379-1406.

    Not in our library10.1152/physrev.90100.2007

  7. 7.

    Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol. 2012;8(8):457-465.

    Not in our library10.1038/nrendo.2012.49

  8. 8.

    Safdar A, Tarnopolsky MA. Exosomes as mediators of the systemic adaptations to endurance exercise. Cold Spring Harb Perspect Med. 2018;8(3):a029827.

    Not in our library10.1101/cshperspect.a029827

  9. 9.

    Safdar A, Saleem A, Tarnopolsky MA. The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nat Rev Endocrinol. 2016;12(9):504-517.

    Not in our library10.1038/nrendo.2016.76

  10. 10.

    Whitham M, Parker BL, Friedrichsen M, et al. Extracellular vesicles provide a means for tissue crosstalk during exercise. Cell Metab. 2018;27(1):237-251.e4.

    Not in our library10.1016/j.cmet.2017.12.001

  11. 11.

    Das DK, Graham ZA, Cardozo CP. Myokines in skeletal muscle physiology and metabolism: recent advances and future perspectives. Acta Physiol (Oxf). 2020;228(2):e13367.

    Not in our library10.1111/apha.13367

  12. 12.

    Eckel J. Myokines in metabolic homeostasis and diabetes. Diabetologia. 2019;62(9):1523-1528.

    Not in our library10.1007/s00125-019-4927-9

  13. 13.

    Garneau L, Aguer C. Role of myokines in the development of skeletal muscle insulin resistance and related metabolic defects in type 2 diabetes. Diabetes Metab. 2019;45(6):505-516.

    Not in our library10.1016/j.diabet.2019.02.006

  14. 14.
    Role of Myokines in Regulating Skeletal Muscle Mass and Function · 2019
    No notice
  15. 15.

    Díaz BB, González DA, Gannar F, Pérez MCR, de León AC. Myokines, physical activity, insulin resistance and autoimmune diseases. Immunol Lett. 2018;203:1-5.

    Not in our library10.1016/j.imlet.2018.09.002

  16. 16.

    Hoffmann C, Weigert C. Skeletal muscle as an endocrine organ: the role of myokines in exercise adaptations. Cold Spring Harb Perspect Med. 2017;7(11):a029793.

    Not in our library10.1101/cshperspect.a029793

  17. 17.

    Rodríguez A, Becerril S, Ezquerro S, Méndez-Giménez L, Frühbeck G. Crosstalk between adipokines and myokines in fat browning. Acta Physiol (Oxf). 2017;219(2):362-381.

    Not in our library10.1111/apha.12686

  18. 18.

    Schnyder S, Handschin C. Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise. Bone. 2015;80:115-125.

    Not in our library10.1016/j.bone.2015.02.008

  19. 19.

    Ahima RS, Park HK. Connecting myokines and metabolism. Endocrinol Metab (Seoul). 2015;30(3):235-245.

    Not in our library10.3803/enm.2015.30.3.235

  20. 20.
    Adipo-Myokines: Two Sides of the Same Coin—Mediators of Inflammation and Mediators of Exercise · 2013
    No notice
  21. 21.

    Pedersen BK. Exercise-induced myokines and their role in chronic diseases. Brain Behav Immun. 2011;25(5):811-816.

    Not in our library10.1016/j.bbi.2011.02.010

  22. 22.

    Trayhurn P, Drevon CA, Eckel J. Secreted proteins from adipose tissue and skeletal muscle - adipokines, myokines and adipose/muscle cross-talk. Arch Physiol Biochem. 2011;117(2):47-56.

    Not in our library10.3109/13813455.2010.535835

  23. 23.

    Hamrick MW. A role for myokines in muscle-bone interactions. Exerc Sport Sci Rev. 2011;39(1):43-47.

    Not in our library10.1097/jes.0b013e318201f601

  24. 24.
    The Role of Exercise-Induced Myokines in Muscle Homeostasis and the Defense against Chronic Diseases · 2010
    No notice
  25. 25.

    Arnold AS, Egger A, Handschin C. PGC-1α and myokines in the aging muscle - a mini-review. Gerontology. 2011;57(1):37-43.

    Not in our library10.1159/000281883

  26. 26.

    Pedersen BK. The diseasome of physical inactivity- and the role of myokines in muscle-fat cross talk. J Physiol. 2009;587(Pt 23):5559-5568.

    Not in our library10.1113/jphysiol.2009.179515

  27. 27.

    Walsh K. Adipokines, myokines and cardiovascular disease. Circ J. 2009;73(1):13-18.

    Not in our library10.1253/circj.cj-08-0961

  28. 28.

    Pedersen BK, Akerström TC, Nielsen AR, Fischer CP. Role of myokines in exercise and metabolism. J Appl Physiol (1985). 2007;103(3):1093-1098.

    Not in our library10.1152/japplphysiol.00080.2007

  29. 29.

    Benatti FB, Pedersen BK. Exercise as an anti-inflammatory therapy for rheumatic diseases-myokine regulation. Nat Rev Rheumatol. 2015;11(2):86-97.

    Not in our library10.1038/nrrheum.2014.193

  30. 30.

    Pedersen BK. Physical activity and muscle-brain crosstalk. Nat Rev Endocrinol. 2019;15(7):383-392.

    Not in our library10.1038/s41574-019-0174-x

  31. 31.

    Whitham M, Febbraio MA. The ever-expanding myokinome: discovery challenges and therapeutic implications. Nat Rev Drug Discov. 2016;15(10):719-729.

    Not in our library10.1038/nrd.2016.153

  32. 32.

    Pal M, Febbraio MA, Whitham M. From cytokine to myokine: the emerging role of interleukin-6 in metabolic regulation. Immunol Cell Biol. 2014;92(4):331-339.

    Not in our library10.1038/icb.2014.16

  33. 33.

    Ruiz-Casado A, Martín-Ruiz A, Pérez LM, Provencio M, Fiuza-Luces C, Lucia A. Exercise and the hallmarks of cancer. Trends Cancer. 2017;3(6):423-441.

    Not in our library10.1016/j.trecan.2017.04.007

  34. 34.

    Fiuza-Luces C, Santos-Lozano A, Joyner M, et al. Exercise benefits in cardiovascular disease: beyond attenuation of traditional risk factors. Nat Rev Cardiol. 2018;15(12):731-743.

    Not in our library10.1038/s41569-018-0065-1

  35. 35.

    Indrakusuma I, Sell H, Eckel J. Novel mediators of adipose tissue and muscle crosstalk. Curr Obes Rep. 2015;4(4):411-417.

    Not in our library10.1007/s13679-015-0174-7

  36. 36.

    Graf C, Ferrari N. Metabolic health-the role of adipo-myokines. Int J Mol Sci. 2019;20(24):6159.

    Not in our library10.3390/ijms20246159

  37. 37.

    Coelho-Junior HJ, Picca A, Calvani R, Uchida MC, Marzetti E. If my muscle could talk: myokines as a biomarker of frailty. Exp Gerontol. 2019;127:110715.

    Not in our library10.1016/j.exger.2019.110715

  38. 38.

    Khan SU, Ghafoor S. Myokines: discovery challenges and therapeutic impediments. J Pak Med Assoc. 2019;69(7):1014-1017.

    Not in our library

  39. 39.

    Henningsen J, Pedersen BK, Kratchmarova I. Quantitative analysis of the secretion of the MCP family of chemokines by muscle cells. Mol Biosyst. 2011;7(2):311-321.

    Not in our library10.1039/c0mb00209g

  40. 40.

    Henningsen J, Rigbolt KT, Blagoev B, Pedersen BK, Kratchmarova I. Dynamics of the skeletal muscle secretome during myoblast differentiation. Mol Cell Proteomics. 2010;9(11):2482-2496.

    Not in our library10.1074/mcp.m110.002113

  41. 41.

    Hojman P, Gehl J, Christensen JF, Pedersen BK. Molecular mechanisms linking exercise to cancer prevention and treatment. Cell Metab. 2018;27(1):10-21.

    Not in our library10.1016/j.cmet.2017.09.015

  42. 42.

    Pedersen L, Idorn M, Olofsson GH, et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab. 2016;23(3):554-562.

    Not in our library10.1016/j.cmet.2016.01.011

  43. 43.

    McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997;387(6628):83-90.

    Not in our library10.1038/387083a0

  44. 44.
    A Mutation in the Myostatin Gene Increases Muscle Mass and Enhances Racing Performance in Heterozygote Dogs · 2007
    No notice
  45. 45.

    Grobet L, Martin LJ, Poncelet D, et al. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet. 1997;17(1):71-74.

    Not in our library10.1038/ng0997-71

  46. 46.

    Kanzleiter T, Rath M, Görgens SW, et al. The myokine decorin is regulated by contraction and involved in muscle hypertrophy. Biochem Biophys Res Commun. 2014;450(2):1089-1094.

    Not in our library10.1016/j.bbrc.2014.06.123

  47. 47.

    Saremi A, Gharakhanloo R, Sharghi S, Gharaati MR, Larijani B, Omidfar K. Effects of oral creatine and resistance training on serum myostatin and GASP-1. Mol Cell Endocrinol. 2010;317(1-2):25-30.

    Not in our library10.1016/j.mce.2009.12.019

  48. 48.

    Hittel DS, Axelson M, Sarna N, Shearer J, Huffman KM, Kraus WE. Myostatin decreases with aerobic exercise and associates with insulin resistance. Med Sci Sports Exerc. 2010;42(11):2023-2029.

    Not in our library10.1249/mss.0b013e3181e0b9a8

  49. 49.

    Serrano AL, Baeza-Raja B, Perdiguero E, Jardí M, Muñoz-Cánoves P. Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell Metab. 2008;7(1):33-44.

    Not in our library10.1016/j.cmet.2007.11.011

  50. 50.

    Broholm C, Mortensen OH, Nielsen S, et al. Exercise induces expression of leukaemia inhibitory factor in human skeletal muscle. J Physiol. 2008;586(8):2195-2201.

    Not in our library10.1113/jphysiol.2007.149781

  51. 51.

    Broholm C, Pedersen BK. Leukaemia inhibitory factor–an exercise-induced myokine. Exerc Immunol Rev. 2010;16:77-85.

    Not in our library

  52. 52.

    Gao S, Durstine JL, Koh HJ, Carver WE, Frizzell N, Carson JA. Acute myotube protein synthesis regulation by IL-6-related cytokines. Am J Physiol Cell Physiol. 2017;313(5):C487-C500.

    Not in our library10.1152/ajpcell.00112.2017

  53. 53.

    Nielsen AR, Mounier R, Plomgaard P, et al. Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle fibre type composition. J Physiol. 2007;584(Pt 1):305-312.

    Not in our library10.1113/jphysiol.2007.139618

  54. 54.

    Haugen F, Norheim F, Lian H, et al. IL-7 is expressed and secreted by human skeletal muscle cells. Am J Physiol Cell Physiol. 2010;298(4):C807-C816.

    Not in our library10.1152/ajpcell.00094.2009

  55. 55.

    Fischer CP. Interleukin-6 in acute exercise and training: what is the biological relevance? Exerc Immunol Rev. 2006;12:6-33.

    Not in our library

  56. 56.

    Fischer CP, Plomgaard P, Hansen AK, Pilegaard H, Saltin B, Pedersen BK. Endurance training reduces the contraction-induced interleukin-6 mRNA expression in human skeletal muscle. Am J Physiol Endocrinol Metab. 2004;287(6):E1189-E1194.

    Not in our library10.1152/ajpendo.00206.2004

  57. 57.

    Keller C, Steensberg A, Hansen AK, Fischer CP, Plomgaard P, Pedersen BK. Effect of exercise, training, and glycogen availability on IL-6 receptor expression in human skeletal muscle. J Appl Physiol (1985). 2005;99(6):2075-2079.

    Not in our library10.1152/japplphysiol.00590.2005

  58. 58.

    Carey AL, Steinberg GR, Macaulay SL, et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes. 2006;55(10):2688-2697.

    Not in our library10.2337/db05-1404

  59. 59.

    Bruce CR, Dyck DJ. Cytokine regulation of skeletal muscle fatty acid metabolism: effect of interleukin-6 and tumor necrosis factor-alpha. Am J Physiol Endocrinol Metab. 2004;287(4):E616-E621.

    Not in our library10.1152/ajpendo.00150.2004

  60. 60.

    Petersen EW, Carey AL, Sacchetti M, et al. Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro: evidence that IL-6 acts independently of lipolytic hormones. Am J Physiol. 2005;288(1):E155-E162.

    Not in our library10.1152/ajpendo.00257.2004

  61. 61.

    van Hall G, Steensberg A, Sacchetti M, et al. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab. 2003;88(7):3005-3010.

    Not in our library10.1210/jc.2002-021687

  62. 62.

    Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005;1(1):15-25.

    Not in our library10.1016/j.cmet.2004.12.003

  63. 63.

    Matthews VB, Aström MB, Chan MH, et al. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia. 2009;52(7):1409-1418.

    Not in our library10.1007/s00125-009-1364-1

  64. 64.

    Nishizawa H, Matsuda M, Yamada Y, et al. Musclin, a novel skeletal muscle-derived secretory factor. J Biol Chem. 2004;279(19):19391-19395.

    Not in our library10.1074/jbc.c400066200

  65. 65.

    Subbotina E, Sierra A, Zhu Z, et al. Musclin is an activity-stimulated myokine that enhances physical endurance. Proc Natl Acad Sci U S A. 2015;112(52):16042-16047.

    Not in our library10.1073/pnas.1514250112

  66. 66.

    Re Cecconi AD, Forti M, Chiappa M, et al Myokine induced by aerobic exercise, retards muscle atrophy during cancer cachexia in mice. Cancers. 2019;11(10):1541.

    Not in our library10.3390/cancers11101541

  67. 67.

    Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007;30(9):464-472.

    Not in our library10.1016/j.tins.2007.06.011

  68. 68.

    Mattson MP. Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. Cell Metab. 2012;16(6): 706-722.

    Not in our library10.1016/j.cmet.2012.08.012

  69. 69.

    Aarsland D, Sardahaee FS, Anderssen S, Ballard C; Alzheimer’s Society Systematic Review group. Is physical activity a potential preventive factor for vascular dementia? A systematic review. Aging Ment Health. 2010;14(4):386-395.

    Not in our library10.1080/13607860903586136

  70. 70.

    Williams JW, Plassman BL, Burke J, Benjamin S. Preventing Alzheimer’s disease and cognitive decline. Evid Rep Technol Assess (Full Rep). 2010;(193):1-727.

    Not in our library

  71. 71.

    Santos-Lozano A, Pareja-Galeano H, Sanchis-Gomar F, et al. Physical activity and Alzheimer disease: a protective association. Mayo Clin Proc. 2016;91(8):999-1020.

    Not in our library10.1016/j.mayocp.2016.04.024

  72. 72.

    Pedersen BK, Saltin B. Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sports. 2015;25 Suppl(3):1-72.

    Not in our library10.1111/sms.12581

  73. 73.

    Voss MW, Nagamatsu LS, Liu-Ambrose T, Kramer AF. Exercise, brain, and cognition across the life span. J Appl Physiol (1985). 2011;111(5):1505-1513.

    Not in our library10.1152/japplphysiol.00210.2011

  74. 74.

    Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002;25(6):295-301.

    Not in our library10.1016/s0166-2236(02)02143-4

  75. 75.

    Smith PJ, Blumenthal JA, Hoffman BM, et al. Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials. Psychosom Med. 2010;72(3):239-252.

    Not in our library10.1097/psy.0b013e3181d14633

  76. 76.

    Snowden M, Steinman L, Mochan K, et al. Effect of exercise on cognitive performance in community-dwelling older adults: review of intervention trials and recommendations for public health practice and research. J Am Geriatr Soc. 2011;59(4):704-716.

    Not in our library10.1111/j.1532-5415.2011.03323.x

  77. 77.

    Aberg MA, Pedersen NL, Torén K, et al. Cardiovascular fitness is associated with cognition in young adulthood. Proc Natl Acad Sci U S A. 2009;106(49):20906-20911.

    Not in our library10.1073/pnas.0905307106

  78. 78.

    Blundell JE, Gibbons C, Caudwell P, Finlayson G, Hopkins M. Appetite control and energy balance: impact of exercise. Obes Rev. 2015;16 Suppl (1):67-76.

    Not in our library10.1111/obr.12257

  79. 79.

    Kelley GA, Kelley KS. Exercise and sleep: a systematic review of previous meta-analyses. J Evid Based Med. 2017;10(1):26-36.

    Not in our library10.1111/jebm.12236

  80. 80.

    Crush EA, Frith E, Loprinzi PD. Experimental effects of acute exercise duration and exercise recovery on mood state. J Affect Disord. 2018;229:282-287.

    Not in our library10.1016/j.jad.2017.12.092

  81. 81.

    Kobilo T, Liu QR, Gandhi K, Mughal M, Shaham Y, van Praag H. Running is the neurogenic and neurotrophic stimulus in environmental enrichment. Learn Mem. 2011;18(9):605-609.

    Not in our library10.1101/lm.2283011

  82. 82.

    Erickson KI, Voss MW, Prakash RS, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A. 2011;108(7):3017-3022.

    Not in our library10.1073/pnas.1015950108

  83. 83.

    Leardini-Tristao M, Charles AL, Lejay A, et al Beneficial effect of exercise on cognitive function during peripheral arterial disease: potential involvement of myokines and microglial anti-inflammatory phenotype enhancement. J Clin Med. 2019;8(5):653.

    Not in our library10.3390/jcm8050653

  84. 84.

    Rai M, Demontis F. Systemic nutrient and stress signaling via myokines and myometabolites. Annu Rev Physiol. 2016;78:85-107.

    Not in our library10.1146/annurev-physiol-021115-105305

  85. 85.

    Makarova JA, Maltseva DV, Galatenko VV, et al. Exercise immunology meets MiRNAs. Exerc Immunol Rev. 2014;20:135-164.

    Not in our library

  86. 86.

    Loprinzi PD, Frith E. A brief primer on the mediational role of BDNF in the exercise-memory link. Clin Physiol Funct Imaging. 2019;39(1):9-14.

    Not in our library10.1111/cpf.12522

  87. 87.

    Neeper SA, Gómez-Pinilla F, Choi J, Cotman C. Exercise and brain neurotrophins. Nature. 1995;373(6510):109.

    Not in our library10.1038/373109a0

  88. 88.
    Exercise-Mediated Neurogenesis in the Hippocampus via BDNF · 2018
    No notice
  89. 89.

    Oliff HS, Berchtold NC, Isackson P, Cotman CW. Exercise-induced regulation of brain-derived neurotrophic factor (BDNF) transcripts in the rat hippocampus. Brain Res Mol Brain Res. 1998;61(1-2):147-153.

    Not in our library10.1016/s0169-328x(98)00222-8

  90. 90.

    Van Hoomissen JD, Chambliss HO, Holmes PV, Dishman RK. Effects of chronic exercise and imipramine on mRNA for BDNF after olfactory bulbectomy in rat. Brain Res. 2003;974(1-2):228-235.

    Not in our library10.1016/s0006-8993(03)02584-8

  91. 91.

    Farmer J, Zhao X, van Praag H, Wodtke K, Gage FH, Christie BR. Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo. Neuroscience. 2004;124(1):71-79.

    Not in our library10.1016/j.neuroscience.2003.09.029

  92. 92.

    Adlard PA, Perreau VM, Cotman CW. The exercise-induced expression of BDNF within the hippocampus varies across life-span. Neurobiol Aging. 2005;26(4):511-520.

    Not in our library10.1016/j.neurobiolaging.2004.05.006

  93. 93.

    Vaynman S, Ying Z, Gomez-Pinilla F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci. 2004;20(10):2580-2590.

    Not in our library10.1111/j.1460-9568.2004.03720.x

  94. 94.

    Vaynman S, Ying Z, Gómez-Pinilla F. Exercise induces BDNF and synapsin I to specific hippocampal subfields. J Neurosci Res. 2004;76(3):356-362.

    Not in our library10.1002/jnr.20077

  95. 95.

    Rasmussen P, Brassard P, Adser H, et al. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp Physiol. 2009;94(10):1062-1069.

    Not in our library10.1113/expphysiol.2009.048512

  96. 96.

    Seifert T, Brassard P, Wissenberg M, et al. Endurance training enhances BDNF release from the human brain. Am J Physiol Regul Integr Comp Physiol. 2010;298(2):R372-R377.

    Not in our library10.1152/ajpregu.00525.2009

  97. 97.

    Pajonk FG, Wobrock T, Gruber O, et al. Hippocampal plasticity in response to exercise in schizophrenia. Arch Gen Psychiatry. 2010;67(2):133-143.

    Not in our library10.1001/archgenpsychiatry.2009.193

  98. 98.

    Wrann CD, White JP, Salogiannnis J, et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab. 2013;18(5):649-659.

    Not in our library10.1016/j.cmet.2013.09.008

  99. 99.

    Moon HY, Becke A, Berron D, et al. Running-induced systemic cathepsin b secretion is associated with memory function. Cell Metab. 2016;24(2):332-340.

    Not in our library10.1016/j.cmet.2016.05.025

  100. 100.

    Suzuki WA. How body affects brain. Cell Metab. 2016;24(2):192-193.

    Not in our library10.1016/j.cmet.2016.07.022

  101. 101.

    Boström P, Wu J, Jedrychowski MP, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463-468.

    Not in our library10.1038/nature10777

  102. 102.
    Irisin – a myth rather than an exercise-inducible myokine · 2015
    No notice
  103. 103.

    Wrann CD. FNDC5/irisin - their role in the nervous system and as a mediator for beneficial effects of exercise on the brain. Brain Plast. 2015;1(1):55-61.

    Not in our library10.3233/bpl-150019

  104. 104.

    Kim HJ, Higashimori T, Park SY, et al. Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes. 2004;53(4):1060-1067.

    Not in our library10.2337/diabetes.53.4.1060

  105. 105.

    Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005;11(2):183-190.

    Not in our library10.1038/nm1166

  106. 106.

    Matthews VB, Allen TL, Risis S, et al. Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance. Diabetologia. 2010;53(11):2431-2441.

    Not in our library10.1007/s00125-010-1865-y

  107. 107.

    Wallenius V, Wallenius K, Ahrén B, et al. Interleukin-6-deficient mice develop mature-onset obesity. Nat Med. 2002;8(1):75-79.

    Not in our library10.1038/nm0102-75

  108. 108.

    Ellingsgaard H, Hauselmann I, Schuler B, et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med. 2011;17(11):1481-1489.

    Not in our library10.1038/nm.2513

  109. 109.

    Mauer J, Chaurasia B, Goldau J, et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol. 2014;15(5):423-430.

    Not in our library10.1038/ni.2865

  110. 110.

    Mauer J, Denson JL, Brüning JC. Versatile functions for IL-6 in metabolism and cancer. Trends Immunol. 2015;36(2):92-101.

    Not in our library10.1016/j.it.2014.12.008

  111. 111.

    Lang Lehrskov L, Lyngbaek MP, Soederlund L, et al. Interleukin-6 delays gastric emptying in humans with direct effects on glycemic control. Cell Metab. 2018;27(6):1201-1211.e3.

    Not in our library10.1016/j.cmet.2018.04.008

  112. 112.

    Steensberg A, Fischer CP, Keller C, Møller K, Pedersen BK. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab. 2003;285(2):E433-E437.

    Not in our library10.1152/ajpendo.00074.2003

  113. 113.

    Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J. 2003;17(8):884-886.

    Not in our library10.1096/fj.02-0670fje

  114. 114.

    Febbraio MA, Pedersen BK. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. FASEB J. 2002;16(11):1335-1347.

    Not in our library10.1096/fj.01-0876rev

  115. 115.

    Keller C, Hellsten Y, Steensberg A, Pedersen BK. Differential regulation of IL-6 and TNF-alpha via calcineurin in human skeletal muscle cells. Cytokine. 2006;36(3-4):141-147.

    Not in our library10.1016/j.cyto.2006.10.014

  116. 116.

    Hidalgo J, Florit S, Giralt M, Ferrer B, Keller C, Pilegaard H. Transgenic mice with astrocyte-targeted production of interleukin-6 are resistant to high-fat diet-induced increases in body weight and body fat. Brain Behav Immun. 2010;24(1):119-126.

    Not in our library10.1016/j.bbi.2009.09.002

  117. 117.

    Señarís RM, Trujillo ML, Navia B, et al. Interleukin-6 regulates the expression of hypothalamic neuropeptides involved in body weight in a gender-dependent way. J Neuroendocrinol. 2011;23(8):675-686.

    Not in our library10.1111/j.1365-2826.2011.02158.x

  118. 118.

    Molinero A, Fernandez-Perez A, Mogas A, et al. Role of muscle IL-6 in gender-specific metabolism in mice. PLoS One. 2017;12(3):e0173675.

    Not in our library10.1371/journal.pone.0173675

  119. 119.

    Timper K, Denson JL, Steculorum SM, et al. IL-6 improves energy and glucose homeostasis in obesity via enhanced central IL-6 trans-signaling. Cell Rep. 2017;19(2):267-280.

    Not in our library10.1016/j.celrep.2017.03.043

  120. 120.

    Pedersen BK. Muscle as a secretory organ. Compr Physiol. 2013;3(3):1337-1362.

    Not in our library10.1002/cphy.c120033

  121. 121.

    Pedersen BK. The physiology of optimizing health with a focus on exercise as medicine. Annu Rev Physiol. 2019;81:607-627.

    Not in our library10.1146/annurev-physiol-020518-114339

  122. 122.

    Fosgerau K, Galle P, Hansen T, et al. Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes. J Endocrinol. 2010;204(3):265-273.

    Not in our library10.1677/joe-09-0413

  123. 123.

    Bays HE. “Sick fat,” metabolic disease, and atherosclerosis. Am J Med. 2009;122(1 Suppl):S26-S37.

    Not in our library10.1016/j.amjmed.2008.10.015

  124. 124.

    Haffner SM. Abdominal adiposity and cardiometabolic risk: do we have all the answers? Am J Med. 2007;120(9 Suppl 1):S10-S16; discussion S16.

    Not in our library10.1016/j.amjmed.2007.06.006

  125. 125.

    Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K. Central obesity and increased risk of dementia more than three decades later. Neurology. 2008;71(14):1057-1064.

    Not in our library10.1212/01.wnl.0000306313.89165.ef

  126. 126.

    Giovannucci E. Metabolic syndrome, hyperinsulinemia, and colon cancer: a review. Am J Clin Nutr. 2007;86(3):s836-s842.

    Not in our library10.1093/ajcn/86.3.836s

  127. 127.

    Xue F, Michels KB. Diabetes, metabolic syndrome, and breast cancer: a review of the current evidence. Am J Clin Nutr. 2007;86(3):s823-s835.

    Not in our library10.1093/ajcn/86.3.823s

  128. 128.

    Pischon T, Boeing H, Hoffmann K, et al. General and abdominal adiposity and risk of death in Europe. N Engl J Med. 2008;359(20):2105-2120.

    Not in our library10.1056/nejmoa0801891

  129. 129.
    Cardiorespiratory fitness and the metabolic syndrome: Roles of inflammation and abdominal obesity. · 2018
    Not checked
  130. 130.

    Wedell-Neergaard AS, Eriksen L, Grønbæk M, Pedersen BK, Krogh-Madsen R, Tolstrup J. Low fitness is associated with abdominal adiposity and low-grade inflammation independent of BMI. PLoS One. 2018;13(1):e0190645.

    Not in our library10.1371/journal.pone.0190645

  131. 131.

    Yudkin JS, Eringa E, Stehouwer CD. “Vasocrine” signalling from perivascular fat: a mechanism linking insulin resistance to vascular disease. Lancet. 2005;365(9473):1817-1820.

    Not in our library10.1016/s0140-6736(05)66585-3

  132. 132.

    Handschin C, Spiegelman BM. The role of exercise and PGC1alpha in inflammation and chronic disease. Nature. 2008;454(7203):463-469.

    Not in our library10.1038/nature07206

  133. 133.

    Olsen RH, Krogh-Madsen R, Thomsen C, Booth FW, Pedersen BK. Metabolic responses to reduced daily steps in healthy nonexercising men. JAMA. 2008;299(11):1261-1263.

    Not in our library10.1001/jama.299.11.1259

  134. 134.

    Nordby P, Auerbach PL, Rosenkilde M, et al. Endurance training per se increases metabolic health in young, moderately overweight men. Obesity (Silver Spring). 2012;20(11):2202-2212.

    Not in our library10.1038/oby.2012.70

  135. 135.

    Ross R, Dagnone D, Jones PJ, et al. Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men. A randomized, controlled trial. Ann Intern Med. 2000;133(2):92-103.

    Not in our library10.7326/0003-4819-133-2-200007180-00008

  136. 136.

    Wedell-Neergaard AS, Lang Lehrskov L, Christensen RH, et al. Exercise-induced changes in visceral adipose tissue mass are regulated by IL-6 signaling: a randomized controlled trial. Cell Metab. 2019;29(4):844-855.e3.

    Not in our library10.1016/j.cmet.2018.12.007

  137. 137.

    Christensen RH, Wedell-Neergaard AS, Lehrskov LL, et al. The role of exercise combined with tocilizumab in visceral and epicardial adipose tissue and gastric emptying rate in abdominally obese participants: protocol for a randomised controlled trial. Trials. 2018;19(1):266.

    Not in our library10.1186/s13063-018-2637-0

  138. 138.

    Christensen RH, Lehrskov LL, Wedell-Neergaard AS, et al. Aerobic exercise induces cardiac fat loss and alters cardiac muscle mass through an interleukin-6 receptor-dependent mechanism: cardiac analysis of a double-blind randomized controlled clinical trial in abdominally obese humans. Circulation. 2019;140(20):1684-1686.

    Not in our library10.1161/circulationaha.119.042287

  139. 139.

    Townsend LK, Wright DC. Looking on the “brite” side exercise-induced browning of white adipose tissue. Pflugers Arch. 2019;471(3):455-465.

    Not in our library10.1007/s00424-018-2177-1

  140. 140.

    Dinas PC, Lahart IM, Timmons JA, et al. Effects of physical activity on the link between PGC-1a and FNDC5 in muscle, circulating Ιrisin and UCP1 of white adipocytes in humans: a systematic review. F1000Res. 2017;6:286.

    Not in our library10.12688/f1000research.11107.1

  141. 141.

    Rao R, Long J, White J, et al. Meteorin-like is a hormone that regulates immune-adipose interactions to Increase BEige Fat Thermogenesis. Cell. 2014;157(6):1279-1291.

    Not in our library10.1016/j.cell.2014.03.065

  142. 142.

    Pedersen BK. Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease. Eur J Clin Invest. 2017;47(8):600-611.

    Not in our library10.1111/eci.12781

  143. 143.

    Karstoft K, Pedersen BK. Skeletal muscle as a gene regulatory endocrine organ. Curr Opin Clin Nutr Metab Care. 2016;19(4):270-275.

    Not in our library10.1097/mco.0000000000000283

  144. 144.

    Karstoft K, Pedersen BK. Exercise and type 2 diabetes: focus on metabolism and inflammation. Immunol Cell Biol. 2016;94(2):146-150.

    Not in our library10.1038/icb.2015.101

  145. 145.

    Knudsen SH, Pedersen BK. Targeting inflammation through a physical active lifestyle and pharmaceuticals for the treatment of type 2 diabetes. Curr Diab Rep. 2015;15(10):82.

    Not in our library10.1007/s11892-015-0642-1

  146. 146.
    Role of IL-6 in Exercise Training- and Cold-Induced UCP1 Expression in Subcutaneous White Adipose Tissue · 2014
    No notice
  147. 147.

    Kristóf E, Klusóczki Á, Veress R, et al. Interleukin-6 released from differentiating human beige adipocytes improves browning. Exp Cell Res. 2019;377(1-2):47-55.

    Not in our library10.1016/j.yexcr.2019.02.015

  148. 148.

    Roberts LD, Boström P, O’Sullivan JF, et al. β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab. 2014;19(1):96-108.

    Not in our library10.1016/j.cmet.2013.12.003

  149. 149.

    Kammoun HL, Febbraio MA. Come on BAIBA light my fire. Cell Metab. 2014;19(1):1-2.

    Not in our library10.1016/j.cmet.2013.12.007

  150. 150.

    Hansen JS, Clemmesen JO, Secher NH, et al. Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans. Mol Metab. 2015;4(8):551-560.

    Not in our library10.1016/j.molmet.2015.06.001

  151. 151.

    Hansen JS, Rutti S, Arous C, et al. Circulating follistatin is liver-derived and regulated by the glucagon-to-insulin ratio. J Clin Endocrinol Metab. 2016;101(2):550-560.

    Not in our library10.1210/jc.2015-3668

  152. 152.

    Hansen JS, Pedersen BK, Xu G, Lehmann R, Weigert C, Plomgaard P. Exercise-induced secretion of FGF21 and follistatin are blocked by pancreatic clamp and impaired in type 2 diabetes. J Clin Endocrinol Metab. 2016;101(7):2816-2825.

    Not in our library10.1210/jc.2016-1681

  153. 153.

    Singh R, Braga M, Pervin S. Regulation of brown adipocyte metabolism by myostatin/follistatin signaling. Front Cell Dev Biol. 2014;2:60.

    Not in our library10.3389/fcell.2014.00060

  154. 154.

    Véniant MM, Sivits G, Helmering J, et al. Pharmacologic effects of FGF21 are independent of the “browning” of white adipose tissue. Cell Metab. 2015;21(5):731-738.

    Not in our library10.1016/j.cmet.2015.04.019

  155. 155.

    Norheim F, Langleite TM, Hjorth M, et al. The effects of acute and chronic exercise on PGC-1α, irisin and browning of subcutaneous adipose tissue in humans. Febs J. 2014;281(3):739-749.

    Not in our library10.1111/febs.12619

  156. 156.

    Vosselman MJ, Hoeks J, Brans B, et al. Low brown adipose tissue activity in endurance-trained compared with lean sedentary men. Int J Obes (Lond). 2015;39(12):1696-1702.

    Not in our library10.1038/ijo.2015.130

  157. 157.

    Schipilow JD, Macdonald HM, Liphardt AM, Kan M, Boyd SK. Bone micro-architecture, estimated bone strength, and the muscle-bone interaction in elite athletes: an HR-pQCT study. Bone. 2013;56(2):281-289.

    Not in our library10.1016/j.bone.2013.06.014

  158. 158.

    Verschueren S, Gielen E, O’Neill TW, et al. Sarcopenia and its relationship with bone mineral density in middle-aged and elderly European men. Osteoporos Int. 2013;24(1):87-98.

    Not in our library10.1007/s00198-012-2057-z

  159. 159.

    Guo B, Zhang ZK, Liang C, et al. Molecular communication from skeletal muscle to bone: a review for muscle-derived myokines regulating bone metabolism. Calcif Tissue Int. 2017;100(2):184-192.

    Not in our library10.1007/s00223-016-0209-4

  160. 160.

    Gomarasca M, Banfi G, Lombardi G. Myokines: the endocrine coupling of skeletal muscle and bone. Adv Clin Chem. 2020;94:155-218.

    Not in our library10.1016/bs.acc.2019.07.010

  161. 161.

    Bialek P, Parkington J, Li X, et al. A myostatin and activin decoy receptor enhances bone formation in mice. Bone. 2014;60:162-171.

    Not in our library10.1016/j.bone.2013.12.002

  162. 162.

    Dankbar B, Fennen M, Brunert D, et al. Myostatin is a direct regulator of osteoclast differentiation and its inhibition reduces inflammatory joint destruction in mice. Nat Med. 2015;21(9):1085-1090.

    Not in our library10.1038/nm.3917

  163. 163.

    De Benedetti F, Rucci N, Del Fattore A, et al. Impaired skeletal development in interleukin-6-transgenic mice: a model for the impact of chronic inflammation on the growing skeletal system. Arthritis Rheum. 2006;54(11):3551-3563.

    Not in our library10.1002/art.22175

  164. 164.

    Jilka RL, Hangoc G, Girasole G, et al. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science. 1992;257(5066):88-91.

    Not in our library10.1126/science.1621100

  165. 165.

    Le Goff B, Blanchard F, Berthelot JM, Heymann D, Maugars Y. Role for interleukin-6 in structural joint damage and systemic bone loss in rheumatoid arthritis. Joint Bone Spine. 2010;77(3):201-205.

    Not in our library10.1016/j.jbspin.2010.03.002

  166. 166.

    Axmann R, Böhm C, Krönke G, Zwerina J, Smolen J, Schett G. Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo. Arthritis Rheum. 2009;60(9):2747-2756.

    Not in our library10.1002/art.24781

  167. 167.

    Palmqvist P, Persson E, Conaway HH, Lerner UH. IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-kappa B ligand, osteoprotegerin, and receptor activator of NF-kappa B in mouse calvariae. J Immunol. 2002;169(6):3353-3362.

    Not in our library10.4049/jimmunol.169.6.3353

  168. 168.

    Saidenberg-Kermanac’h N, Cohen-Solal M, Bessis N, De Vernejoul MC, Boissier MC. Role for osteoprotegerin in rheumatoid inflammation. Joint Bone Spine. 2004;71(1):9-13.

    Not in our library10.1016/s1297-319x(03)00131-3

  169. 169.

    Lombardi G, Sanchis-Gomar F, Perego S, Sansoni V, Banfi G. Implications of exercise-induced adipo-myokines in bone metabolism. Endocrine. 2016;54(2):284-305.

    Not in our library10.1007/s12020-015-0834-0

  170. 170.

    Yakar S, Rosen CJ, Beamer WG, et al. Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest. 2002;110(6):771-781.

    Not in our library10.1172/jci15463

  171. 171.

    Perrini S, Laviola L, Carreira MC, Cignarelli A, Natalicchio A, Giorgino F. The GH/IGF1 axis and signaling pathways in the muscle and bone: mechanisms underlying age-related skeletal muscle wasting and osteoporosis. J Endocrinol. 2010;205(3):201-210.

    Not in our library10.1677/joe-09-0431

  172. 172.

    Chan CY, Masui O, Krakovska O, et al. Identification of differentially regulated secretome components during skeletal myogenesis. Mol Cell Proteomics. 2011;10(5):M110.004804.

    Not in our library10.1074/mcp.m110.004804

  173. 173.

    Chan CY, McDermott JC, Siu KW. Secretome analysis of skeletal myogenesis using SILAC and shotgun proteomics. Int J Proteomics. 2011;2011:329467.

    Not in our library10.1155/2011/329467

  174. 174.

    Kaji H. Effects of myokines on bone. Bonekey Rep. 2016;5:826.

    Not in our library10.1038/bonekey.2016.48

  175. 175.

    Wasserman DH, Lacy DB, Colburn CA, Bracy D, Cherrington AD. Efficiency of compensation for absence of fall in insulin during exercise. Am J Physiol. 1991;261(5 Pt 1):E587-E597.

    Not in our library10.1152/ajpendo.1991.261.5.e587

  176. 176.

    Febbraio MA, Hiscock N, Sacchetti M, Fischer CP, Pedersen BK. Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes. 2004;53(7):1643-1648.

    Not in our library10.2337/diabetes.53.7.1643

  177. 177.

    Steensberg A, Fischer CP, Sacchetti M, et al Acute interleukin-6 administration does not impair muscle glucose uptake or whole body glucose disposal in healthy humans. J Physiol. 2003;548(Pt 2):631-638.

    Not in our library10.1113/jphysiol.2002.032938

  178. 178.

    Peppler WT, Townsend LK, Meers GM, et al. Acute administration of IL-6 improves indices of hepatic glucose and insulin homeostasis in lean and obese mice. Am J Physiol Gastrointest Liver Physiol. 2019;316(1):G166-G178.

    Not in our library10.1152/ajpgi.00097.2018

  179. 179.

    Woerle HJ, Albrecht M, Linke R, et al. Importance of changes in gastric emptying for postprandial plasma glucose fluxes in healthy humans. Am J Physiol Endocrinol Metab. 2008;294(1): E103-E109.

    Not in our library10.1152/ajpendo.00514.2007

  180. 180.

    Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR, Pedersen BK. Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. Diabetes. 2005;54(10):2939-2945.

    Not in our library10.2337/diabetes.54.10.2939

  181. 181.

    Bouzakri K, Plomgaard P, Berney T, Donath MY, Pedersen BK, Halban PA. Bimodal effect on pancreatic β-cells of secretory products from normal or insulin-resistant human skeletal muscle. Diabetes. 2011;60(4):1111-1121.

    Not in our library10.2337/db10-1178

  182. 182.

    Rutti S, Dusaulcy R, Hansen JS, et al. Angiogenin and Osteoprotegerin are type II muscle specific myokines protecting pancreatic beta-cells against proinflammatory cytokines. Sci Rep. 2018;8(1):10072.

    Not in our library10.1038/s41598-018-28117-2

  183. 183.

    Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11(2):98-107.

    Not in our library10.1038/nri2925

  184. 184.

    Eguchi K, Manabe I. Macrophages and islet inflammation in type 2 diabetes. Diabetes Obes Metab. 2013;15 Suppl (3):152-158.

    Not in our library10.1111/dom.12168

  185. 185.

    Ehses JA, Perren A, Eppler E, et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes. 2007;56(9):2356-2370.

    Not in our library10.2337/db06-1650

  186. 186.

    Westwell-Roper CY, Ehses JA, Verchere CB. Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1β production and β-cell dysfunction. Diabetes. 2014;63(5):1698-1711.

    Not in our library10.2337/db13-0863

  187. 187.

    Alluisi EA, Beisel WR, Caldwell LS. Effects of sandfly fever on isometric muscular strength, endurance, and recovery. J Mot Behav. 1980;12(1):1-11.

    Not in our library10.1080/00222895.1980.10735200

  188. 188.

    Cabrera SM, Wang X, Chen YG, et al.; Type 1 Diabetes TrialNet Canakinumab Study Group; AIDA Study Group. Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset. Eur J Immunol. 2016;46(4): 1030-1046.

    Not in our library10.1002/eji.201546005

  189. 189.

    Urwyler SA, Schuetz P, Ebrahimi F, Donath MY, Christ-Crain M. Interleukin-1 antagonism decreases cortisol levels in obese individuals. J Clin Endocrinol Metab. 2017;102(5):1712-1718.

    Not in our library10.1210/jc.2016-3931

  190. 190.

    Everett BM, Donath MY, Pradhan AD, et al. Anti-inflammatory therapy with canakinumab for the prevention and management of diabetes. J Am Coll Cardiol. 2018;71(21):2392-2401.

    Not in our library10.1016/j.jacc.2018.03.002

  191. 191.

    Ellingsgaard H, Ehses JA, Hammar EB, et al. Interleukin-6 regulates pancreatic alpha-cell mass expansion. Proc Natl Acad Sci U S A. 2008;105(35):13163-13168.

    Not in our library10.1073/pnas.0801059105

  192. 192.

    Izumiya Y, Hopkins T, Morris C, et al. Fast/Glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice. Cell Metab. 2008;7(2):159-172.

    Not in our library10.1016/j.cmet.2007.11.003

  193. 193.

    Shimano M, Ouchi N, Walsh K. Cardiokines: recent progress in elucidating the cardiac secretome. Circulation. 2012;126(21):e327-e332.

    Not in our library10.1161/circulationaha.112.150656

  194. 194.

    Ouchi N, Oshima Y, Ohashi K, et al. Follistatin-like 1, a secreted muscle protein, promotes endothelial cell function and revascularization in ischemic tissue through a nitric-oxide synthase-dependent mechanism. J Biol Chem. 2008;283(47):32802-32811.

    Not in our library10.1074/jbc.m803440200

  195. 195.

    Oshima Y, Ouchi N, Sato K, Izumiya Y, Pimentel DR, Walsh K. Follistatin-like 1 is an Akt-regulated cardioprotective factor that is secreted by the heart. Circulation. 2008;117(24):3099-3108.

    Not in our library10.1161/circulationaha.108.767673

  196. 196.

    El-Armouche A, Ouchi N, Tanaka K, et al. Follistatin-like 1 in chronic systolic heart failure: a marker of left ventricular remodeling. Circ Heart Fail. 2011;4(5):621-627.

    Not in our library10.1161/circheartfailure.110.960625

  197. 197.

    Tanaka K, Valero-Muñoz M, Wilson RM, et al. Follistatin like 1 regulates hypertrophy in heart failure with preserved ejection fraction. JACC Basic Transl Sci. 2016;1(4):207-221.

    Not in our library10.1016/j.jacbts.2016.04.002

  198. 198.

    Ogura Y, Ouchi N, Ohashi K, et al. Therapeutic impact of follistatin-like 1 on myocardial ischemic injury in preclinical models. Circulation. 2012;126(14):1728-1738.

    Not in our library10.1161/circulationaha.112.115089

  199. 199.

    Seki M, Powers JC, Maruyama S, et al. Acute and chronic increases of circulating FSTL1 normalize energy substrate metabolism in pacing-induced heart failure. Circ Heart Fail. 2018;11(1):e004486.

    Not in our library10.1161/circheartfailure.117.004486

  200. 200.
    Exercise‐stimulated interleukin‐15 is controlled by AMPK and regulates skin metabolism and aging · 2015
    No notice
  201. 201.

    Duggal NA, Niemiro G, Harridge SDR, Simpson RJ, Lord JM. Can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity? Nat Rev Immunol. 2019;19(9):563-572.

    Not in our library10.1038/s41577-019-0177-9

  202. 202.

    McCarthy DA, Dale MM. The leucocytosis of exercise. A review and model. Sports Med. 1988;6(6):333-363.

    Not in our library10.2165/00007256-198806060-00002

  203. 203.

    Pedersen BK, Hoffman-Goetz L. Exercise and the immune system: regulation, integration, and adaptation. Physiol Rev. 2000;80(3):1055-1081.

    Not in our library10.1152/physrev.2000.80.3.1055

  204. 204.

    Nieman DC, Fagoaga OR, Butterworth DE, et al. Carbohydrate supplementation affects blood granulocyte and monocyte trafficking but not function after 2.5 h or running. Am J Clin Nutr. 1997;66(1):153-159.

    Not in our library10.1093/ajcn/66.1.153

  205. 205.

    Nehlsen-Cannarella SL, Fagoaga OR, Nieman DC, et al. Carbohydrate and the cytokine response to 2.5 h of running. J Appl Physiol (1985). 1997;82(5):1662-1667.

    Not in our library10.1152/jappl.1997.82.5.1662

  206. 206.

    Fischer CP, Hiscock NJ, Penkowa M, et al. Supplementation with vitamins C and E inhibits the release of interleukin-6 from contracting human skeletal muscle. J Physiol. 2004;558(Pt 2):633-645.

    Not in our library10.1113/jphysiol.2004.066779

  207. 207.

    Petersen AM, Pedersen BK. The role of IL-6 in mediating the anti-inflammatory effects of exercise. J Physiol Pharmacol. 2006;57 Suppl (10):43-51.

    Not in our library

  208. 208.

    Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol (1985). 2005;98(4):1154-1162.

    Not in our library10.1152/japplphysiol.00164.2004

  209. 209.

    Pedersen BK, Steensberg A, Keller P, et al. Muscle-derived interleukin-6: lipolytic, anti-inflammatory and immune regulatory effects. Pflugers Arch. 2003;446(1):9-16.

    Not in our library10.1007/s00424-002-0981-z

  210. 210.

    Pedersen BK. The anti-inflammatory effect of exercise: its role in diabetes and cardiovascular disease control. Essays Biochem. 2006;42:105-117.

    Not in our library10.1042/bse0420105

  211. 211.

    Dinarello CA. The interleukin-1 family: 10 years of discovery. Faseb J. 1994;8(15):1314-1325.

    Not in our library

  212. 212.

    Opp MR, Smith EM, Hughes TK Jr. Interleukin-10 (cytokine synthesis inhibitory factor) acts in the central nervous system of rats to reduce sleep. J Neuroimmunol. 1995;60(1-2):165-168.

    Not in our library10.1016/0165-5728(95)00066-b

  213. 213.

    Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC, Dinarello CA. Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood. 1990;75(1):40-47.

    Not in our library

  214. 214.

    Mizuhara H, O’Neill E, Seki N, et al. T cell activation-associated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6. J Exp Med. 1994;179(5):1529-1537.

    Not in our library10.1084/jem.179.5.1529

  215. 215.

    Han MS, White A, Perry RJ, et al. Regulation of adipose tissue inflammation by interleukin 6. Proc Natl Acad Sci U S A. 2020;117(6):2751-2760.

    Not in our library10.1073/pnas.1920004117

  216. 216.

    Rosenkilde M, Nordby P, Stallknecht B. Maintenance of improvements in fitness and fatness 1 year after a 3-month lifestyle intervention in overweight men. Eur J Clin Nutr. 2016;70(10):1212-1214.

    Not in our library10.1038/ejcn.2016.64

  217. 217.

    Laye MJ, Thyfault JP, Stump CS, Booth FW. Inactivity induces increases in abdominal fat. J Appl Physiol (1985). 2007;102(4):1341-1347.

    Not in our library10.1152/japplphysiol.01018.2006

  218. 218.

    Krogh-Madsen R, Pedersen M, Solomon TP, et al. Normal physical activity obliterates the deleterious effects of a high-caloric intake. J Appl Physiol (1985). 2014;116(3):231-239.

    Not in our library10.1152/japplphysiol.00155.2013

  219. 219.

    Krogh-Madsen R, Thyfault JP, Broholm C, et al. A 2-wk reduction of ambulatory activity attenuates peripheral insulin sensitivity. J Appl Physiol (1985). 2010;108(5):1034-1040.

    Not in our library10.1152/japplphysiol.00977.2009

  220. 220.

    Harder-Lauridsen NM, Nielsen ST, Mann SP, et al. The effect of alternate-day caloric restriction on the metabolic consequences of 8 days of bed rest in healthy lean men: a randomized trial. J Appl Physiol (1985). 2017;122(2):230-241.

    Not in our library10.1152/japplphysiol.00846.2016

  221. 221.

    Christensen RH, Wedell-Neergaard AS, Lehrskov LL, et al Effect of aerobic and resistance exercise on cardiac adipose tissues: secondary analyses from a randomized clinical trial. JAMA Cardiol. 2019;4(8):778-787.

    Not in our library10.1001/jamacardio.2019.2074

  222. 222.

    Moore SC, Lee IM, Weiderpass E, et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern Med. 2016;176(6):816-825.

    Not in our library10.1001/jamainternmed.2016.1548

  223. 223.

    Christensen JF, Simonsen C, Hojman P. Exercise training in cancer control and treatment. Compr Physiol. 2018;9(1):165-205.

    Not in our library10.1002/cphy.c180016

  224. 224.

    Hojman P, Dethlefsen C, Brandt C, Hansen J, Pedersen L, Pedersen BK. Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. Am J Physiol Endocrinol Metab. 2011;301(3):E504-E510.

    Not in our library10.1152/ajpendo.00520.2010

  225. 225.

    Aoi W, Naito Y, Takagi T, et al. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise. Gut. 2013;62(6):882-889.

    Not in our library10.1136/gutjnl-2011-300776

  226. 226.

    Lucia A, Ramírez M. Muscling in on cancer. N Engl J Med. 2016;375(9):892-894.

    Not in our library10.1056/nejmcibr1606456

  227. 227.

    Manole E, Ceafalan LC, Popescu BO, Dumitru C, Bastian AE. Myokines as possible therapeutic targets in cancer cachexia. J Immunol Res. 2018;2018:8260742.

    Not in our library10.1155/2018/8260742

  228. 228.

    Cook KS, Min HY, Johnson D, et al. Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science. 1987;237(4813):402-405.

    Not in our library10.1126/science.3299705

  229. 229.

    Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425-432.

    Not in our library10.1038/372425a0

  230. 230.

    Scherer PE. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes. 2006;55(6):1537-1545.

    Not in our library10.2337/db06-0263

  231. 231.
    Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication · 2019
    Not checked
  232. 232.

    Weigert C, Hoene M, Plomgaard P. Hepatokines-a novel group of exercise factors. Pflugers Arch. 2019;471(3):383-396.

    Not in our library10.1007/s00424-018-2216-y

  233. 233.

    Jespersen NZ, Larsen TJ, Peijs L, et al. A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metab. 2013;17(5):798-805.

    Not in our library10.1016/j.cmet.2013.04.011

  234. 234.

    Deshmukh AS, Peijs L, Beaudry JL, et al. Proteomics-based comparative mapping of the secretomes of human brown and white adipocytes reveals EPDR1 as a novel batokine. Cell Metab. 2019;30(5):963-975.e7.

    Not in our library10.1016/j.cmet.2019.10.001

Cited by papers we hold 12

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.