Exercise training mode effects on myokine expression in healthy adults:A systematic review with meta-analysis

Background:The benefits of exercise are well known;however,many of the underlying molecular mechanisms are not fully understood.Skeletal muscle secretes myokines,which mediate muscleorgan crosstalk.Myokines regulate satellite-cell proliferation and migration,inflammatory cascade,insulin secretion,angiogenesis,fatty oxidation,and cancer suppression.To date,the effects of different exercise modes(namely,aerobic and resistance exercise)on myokine response remain to be elucidated.This is crucial considering the clinical implementation of exercise to enhance general health and wellbeing and as a medical treatment.Methods:A systematic search was undertaken in PubMed,MEDLINE,CINAHL,Embase,SPORTDiscus,andWeb of Science in April 2023.Eligible studies examining the effects of a single bout of exercise on interleukin15(IL-15),irisin,secreted protein acidic and rich in cysteine(SPARC),oncostatinM(OSM),and decorin were included.A random-effects meta-analysis was also undertaken to quantify the magnitude of change.Results:Sixty-two studies were included(n=1193).Overall,exercise appeared to induce small to large increases in myokine expression,with effects observed immediately after to 60 min post-exercise,although these were mostly not statistically significant.Both aerobic and resistance exercise resulted in changes in myokine levels,without any significant difference between training modes,and with the magnitude of change differing across myokines.Myokine levels returned to baseline levels within 180 min to 24 h post-exercise.However,owing to potential sources of heterogeneity,most changes were not statistically significant,indicating that precise conclusions cannot be drawn.Conclusion:Knowledge is limited but expanding with respect to the impact of overall and specific effects of exercise on myokine expression at different time points in the systemic circulation.Further research is required to investigate the effects of different exercise modes at multiple time points on myokine response.

Interaction between inflammatory bowel disease,physical activity,and myokines:Assessment of serum irisin levels

Inflammatory bowel disease(IBD),including Crohn’s disease and ulcerative colitis,showed a wide spectrum of intestinal and extra-intestinal manifestations,which rendered the patients physically inactive and impaired their quality of life.It has been found that physical activity is a non-pharmacological intervention that improves the quality of life for those patients.Irisin is one member of the myokines secreted by muscle contraction during exercise and could be used as an antiinflammatory biomarker in assessing the physical activity of IBD patients.In addition,experimental studies showed that exogenous irisin significantly decreased the inflammatory markers and the histological changes of the intestinal mucosa observed in experimental colitis.Furthermore,irisin produces changes in the diversity of the microbiota.Therefore,endogenous or exogenous irisin,via its anti-inflammatory effects,will improve the health of IBD patients and will limit the barriers to physical activity in patients with IBD.

Interplay of adipokines and myokines in cancer pathophysiology: Emerging therapeutic implications

Excess body weight constitutes a worldwide health problem with epidemic proportions impacting on the risk and prognosis of several disease states including malignancies. It is believed that the metabolic changes associated with weight gain, particularly visceral obesity, and physical inactivity could lead to dysfunctional adipose and muscle tissues causing insulin resistance, low-grade chronic inflammation and abnormal secretion of adipokines and myokines. The complex paracrine and endocrine interconnection between adipokines and myokines reflects a yin-yang balance with important implications in processes such as lipolysis control, insulin sensitivity and prevention from obesity-driven chronic low-grade inflammation and cancer promotion through anti-inflammatory adipokines and myokines. Furthermore, the complex pathophysiology of cancer cachexia is based on the interplay between muscle and adipose tissue mediated by free fatty acids, various adipokines and myokines. The purpose of this editorial is to explore the role of the adipose and muscle tissue interplay in carcinogenesis, cancer progression and cachexia, and to examine the mechanisms underpinning their association with malignancy. Understanding ofthe mechanisms connecting the interplay of adipokines and myokines with cancer pathophysiology is expected to be of importance in the development of therapeutic strategies against cancer cachexia. Advances in the field of translational investigation may lead to tangible benefits to obese and inactive persons who are at increased risk of cancer as well as to cancer patients with cachexia.

Effects of Common Myokines on Diabetes Mellitus

Diabetes mellitus, a type of chronic metabolic disease, is occurring more frequently and causes severe threats to human health. In vivo, exercise can stimulate skeletal muscle cells to secrete and release myokines into blood circulation, which will participate in metabolism and act on multiple organs or systems. Recently, the relationship between myokines and diabetes mellitus was a hot research topic, and myokines may be potential targets for the diagnosis, monitoring, prevention and treatment of diabetes mellitus. In this review, we elucidated the multiple effects of common myokines in the pathogenesis and therapy of diabetes mellitus, which will provide a theoretical foundation of the mechanism in the positive effects of exercises on humans.

Myokines:metabolic regulation in obesity and type 2 diabetes

Skeletal muscle plays a vital role in the regulation of systemic metabolism,partly through its secretion of endocrine factors which are collectively known as myokines.Altered myokine levels are associated with metabolic diseases,such as type 2 diabetes(T2D).The significance of interorgan crosstalk,particularly through myokines,has emerged as a fundamental aspect of nutrient and energy homeostasis.However,a comprehensive understanding of myokine biology in the setting of obesity and T2D remains a major challenge.In this review,we discuss the regulation and biological functions of key myokines that have been extensively studied during the past two decades,namely interleukin 6(IL-6),irisin,myostatin(MSTN),growth differentiation factor 11(GDF11),fibroblast growth factor 21(FGF21),apelin,brain-derived neurotrophic factor(BDNF),meteorin-like(Metrnl),secreted protein acidic and rich in cysteine(SPARC),β-aminoisobutyric acid(BAIBA),Musclin,and Dickkopf 3(Dkk3).Related to these,we detail the role of exercise in myokine expression and secretion together with their contributions to metabolic physiology and disease.Despite significant advancements in myokine research,many myokines remain challenging to measure accurately and investigate thoroughly.Hence,new research techniques and detection methods should be developed and rigorously tested.Therefore,developing a comprehensive perspective on myokine biology is crucial,as this will likely offer new insights into the pathophysiological mechanisms underlying obesity and T2D and may reveal novel targets for therapeutic interventions.

Myokine Response to Blood-Flow Restricted Resistance Exercise in Younger and Older Males in an Untrained and Resistance-Trained State:A Pilot Study

Purpose The purpose of this study was to examine the response of myokines to blood-flow restricted resistance-exercise(BFR-RE)in younger and older males before and after completing a 12-week resistance-training program.Methods There were 8 younger(24.8±3.9 yrs)and 7 older(68.3±5.0 yrs)untrained male participants completed this study.Anthropometric and maximal strength(1RM)measurements were collected before and after a 12-week,supervised,progres-sive full-body resistance-training program.As well,an acute bout of full-body BFR-RE was performed with venipuncture blood samples collected before and immediately following the BFR-RE,followed by sampling at 3,6,24 and 48 h.Results The 12-week training program stimulated a 32.2%increase in average strength and 30%increase in strength per kg of fat free mass.The response of particular myokines to the acute bout of BFR-RE was influenced training status(IL-4,untrained=78.1±133.2 pg/mL vs.trained=59.8±121.6 pg/mL,P=0.019;IL-7,untrained=3.46±1.8 pg/mL vs.trained=2.66±1.3 pg/mL,P=0.047)or both training and age(irisin,P=0.04;leukemia inhibitory factor,P<0.001).As well,changes in strength per kg of fat free mass were correlated with area under the curve for IL-4(r=0.537;P=0.039),IL-6(r=0.525;P=0.044)and LIF(r=−0.548;P=0.035)in the untrained condition.Conclusion This study identified that both age and training status influence the myokine response to an acute bout of BFR-RE with the release of IL-4,IL-6 and LIF in the untrained state being associated with changes in strength per kg of fat free mass.

Suppressive effects of exercise-conditioned serum on cancer cells:A narrative review of the influence of exercise mode,volume,and intensity

Cancer is a major cause of morbidity and mortality worldwide,and the incidence is increasing,highlighting the need for effective strategies to treat this disease.Exercise has emerged as fundamental therapeutic medicine in the management of cancer,associated with a lower risk of recur-rence and increased survival.Several avenues of research demonstrate reduction in growth,proliferation,and increased apoptosis of cancer cells,including breast,prostate,colorectal,and lung cancer,when cultured by serum collected after exercise in vitro(i.e.,the cultivation of cancer cell lines in an experimental setting,which simplifies the biological system and provides mechanistic insight into cell responses).The underlying mechanisms of exercise-induced cancer suppressive effects may be attributed to the alteration in circulating factors,such as skeletal muscle-induced cytokines(i.e.,myokines)and hormones.However,exercise-induced tumor suppressive effects and detailed information about training interventions are not well investigated,constraining more precise application of exercise medicine within clinical oncology.To date,it remains unclear what role different training modes(i.e.,resistance and aerobic training)as well as volume and intensity have on exercise-condi-tioned serum and its effects on cancer cells.Nevertheless,the available evidence is that a single bout of aerobic training at moderate to vigorous intensity has cancer suppressive effects,while for chronic training interventions,exercise volume appears to be an influential candidate driving cancer inhibitory effects regardless of training mode.Insights for future research investigating training modes,volume and intensity are provided to further our understanding of the effects of exercise-conditioned serum on cancer cells.

Exercise training-induced changes in exerkine concentrations may be relevant to the metabolic control of type 2 diabetes mellitus patients:A systematic review and meta-analysis of randomized controlled trials

Background:This study investigates the effects of exercise training on exerkines in patients with type 2 diabetes mellitus to determine the optimal exercise prescription.Methods:A systematic search for relevant studies was performed in 3 databases.Randomized controlled trials investigating the effects of exercise training on at least one of the following exerkines were included:adiponectin,apelin,brain-derived neurotrophic factor,fetuin-A,fibroblast growth factor-21,follistatin,ghrelin,interleukin(IL)-6,IL-8,IL-10,IL-15,IL-18,leptin,myostatin,omentin,resistin,retinol-binding protein 4,tumor necrosis factor-α,and visfatin.Results:Forty randomized controlled trials were selected for data extraction(n=2160).Exercise training induces changes in adiponectin,fetuin-A,fibroblast growth factor-21,IL-6,IL-10,leptin,resistin,and tumor necrosis factor-a levels but has no significant effects on apelin,IL-18,and ghrelin compared to controls.Physical exercise training favored large and positive changes in pooled exerkines(i.e.,an overall effect size calculated from several exerkine s)(Hedge’s g=1.02,95%confidence interval(95%CI):0.76-1.28),which in turn were related to changes in glycated hemoglobin(mean difference(MD)=-0.81%,95%CI:-0.95%to-0.67%),fasting glucose(MD=-23.43 mg/dL,95%CI:-30.07 mg/dL to-16.80 mg/dL),waist circumference(MD=-3.04 cm,95%CI:-4.02 cm to-2.07 cm),and body mass(MD=-1.93 kg,95%CI:-2.00 kg to-1.86 kg).Slightly stronger effects were observed with aerobic,resistance,or high-intensity interval protocols at moderate-to vigorous-intensity and with programs longer than 24 weeks that comprise at least 3 sessions per week and more than 60 min per session.Conclusion:Exercise training represents an anti-inflammatory therapy and metabolism-improving strategy with minimal side effects for patients with type 2 diabetes mellitus.

Magnetic mitohormesis:A non-invasive therapy for inflammatory disorders?

An organism’s survival depends on its ability to adapt to stress.Mitochondria are the cellular integrators of environmental stressors that ultimately translate their responses at the organismal level,and are thus central to the process whereby organisms adapt to their respective environments.Mitochondria produce molecular energy via oxidative phosphorylation that then allows cells to biosynthetically respond and adapt to changes in their environment.Reactive oxygen species(ROS)are by-products of oxidative phosphorylation that can be either beneficial or damaging,depending on the context;ROS are hence both the conveyors of environmental stress as well as cellular“adaptogens”.Mitohormesis refers to the process whereby low levels of oxidative stress spur survival adaptations,whereas excessive levels stymie survival.Low energy and frequency pulsing electromagnetic fields have been recently shown capable of stimulating mitochondrial respiration and ROS production and instilling mitohormetic survival adaptations,similarly to,yet independently of,exercise,opening avenues for the future development of Magnetic Mitohormetic interventions for the improvement of human health.This viewpoint explores the possibilities and nuances of magnetic-based therapies as a form of clinical intervention to non-invasively activate magnetic mitohormesis for the management of chronic diseases.

Impact of a single bout of high-intensity interval exercise and short-term interval training on interleukin-6, FNDC5, and METRNL mRNA expression in human skeletal muscle

Background: Exercise promotes numerous phenotypic adaptations in skeletal muscle that contribute to improved function and metabolic capacity. An emerging body of evidence suggests that skeletal muscle also releases a myriad of factors during exercise, termed "myokines". The purpose of this study was to examine the effects of high-intensity interval training(HIIT) on the acute regulation of the mRNA expression of several myokines, including the prototypical myokine interleukin-6(IL-6), and recently identified myokines fibronectin type III domain-containing protein 5(FNDC5)(irisin) and meteorin-like protein(METRNL).Methods: Both before and after a 20-day period of twice-daily high-volume HIIT, 9 healthy males(20.5 ± 1.5 years performed a standardized bout of high-intensity interval exercise(HIIE; 5 × 4 min at ~80% pretraining peak power output) with skeletal muscle biopsy samples(vastus lateralis) obtained at rest, immediately following exercise, and at 3 h recovery.Results: Before training, a single bout of HIIE increased IL-6(p < 0.05) and METRNL(p < 0.05) mRNA expression measured at 3 h recovery when compared to rest. Following 20 days of HIIT, IL-6 and FNDC5 mRNA were increased at 3 h recovery from the standardized HIIE bout when compared to rest(both p < 0.05). Resting METRNL and FNDC5 mRNA expression were higher following training(p < 0.05), and there was an overall increase in FNDC5 mRNA post-training(main effect of training, p < 0.05).Conclusion: In human skeletal muscle(1) an acute bout of HIIE can induce upregulation of skeletal muscle IL-6 mRNA both before and after a period of intensified HIIT;(2) Resting and overall FNDC5 mRNA expression is increased by 20 days of HIIT; and(3) METRNL mRNA expression is responsive to both acute HIIE and short-term intense HIIT. Future studies are needed to confirm these findings at the protein and secretion level in humans.

Skeletal muscle-derived cells repair peripheral nerve defects in mice

Skeletal muscle-derived cells have strong secretory function,while skeletal muscle-derived stem cells,which are included in muscle-derived cells,can differentiate into Schwann cell-like cells and other cell types.However,the effect of muscle-derived cells on peripheral nerve defects has not been reported.In this study,5-mm-long nerve defects were created in the right sciatic nerves of mice to construct a peripheral nerve defect model.Adult female C57BL/6 mice were randomly divided into four groups.For the muscle-derived cell group,muscle-derived cells were injected into the catheter after the cut nerve ends were bridged with a polyurethane catheter.For external oblique muscle-fabricated nerve conduit and polyurethane groups,an external oblique muscle-fabricated nerve conduit or polyurethane catheter was used to bridge the cut nerve ends,respectively.For the sham group,the sciatic nerves on the right side were separated but not excised.At 8 and 12 weeks post-surgery,distributions of axons and myelin sheaths were observed,and the nerve diameter was calculated using immunofluorescence staining.The number,diameter,and thickness of myelinated nerve fibers were detected by toluidine blue staining and transmission electron microscopy.Muscle fiber area ratios were calculated by Masson’s trichrome staining of gastrocnemius muscle sections.Sciatic functional index was recorded using walking footprint analysis at 4,8,and 12 weeks after operation.The results showed that,at 8 and 12 weeks after surgery,myelin sheaths and axons of regenerating nerves were evenly distributed in the muscle-derived cell group.The number,diameter,and myelin sheath thickness of myelinated nerve fibers,as well as gastrocnemius muscle wet weight and muscle area ratio,were significantly higher in the muscle-derived cell group compared with the polyurethane group.At 4,8,and 12 weeks post-surgery,sciatic functional index was notably increased in the muscle-derived cell group compared with the polyurethane group.These criteria of the muscle-derived cell group were not significantly different from the external oblique muscle-fabricated nerve conduit group.Collectively,these data suggest that muscle-derived cells effectively accelerated peripheral nerve regeneration.This study was approved by the Animal Ethics Committee of Plastic Surgery Hospital,Chinese Academy of Medical Sciences(approval No.040)on September 28,2016.

Relationship between circulating irisin levels and overweight/obesity: A meta-analysis

BACKGROUND Currently, the findings about irisin as a novel myokine related to obesity are inconsistent in overweight/obese people. To our knowledge, no systematic analysis has been conducted to evaluate the relationship between irisin levels and overweight/obesity. AIM To evaluate the association between circulating irisin levels and overweight/obesity. METHODS The Cochrane Library, MEDLINE, SCOPUS, and the ISI Web of Science were searched to retrieve all of the studies associated with circulating irisin levels and overweight/obesity. Standard mean difference values and 95% confidence intervals (CI) were estimated and pooled using meta-analysis methodology. RESULTS A total of 18 studies were included in our meta-analysis containing 1005 cases and 1242 controls. Our analysis showed that the circulating irisin level in overweight/obese people was higher than that in overall healthy controls (random effects MD = 0.63;95%CI: 0.22-1.05;P = 0.003). In the subgroup analysis by ethnicity, the irisin level was higher in overweight/obesity people than that in controls in Africa (random effects MD = 3.41;95%CI: 1.23-5.59;P < 0.05) but not in European, Asian, or American populations. In addition, in a subgroup analysis by age, the results showed that obese children exhibited a higher irisin level than controls (random effects MD = 0.86;95%CI: 0.28-1.43;P < 0.05). CONCLUSION This meta-analysis provides evidence that circulating irisin is higher in obese individuals compared to healthy controls and it is important to identify the relationship between circulating irisin levels and overweight/obesity in predicting overweight/obesity.

Exercise and glucagon-like peptide-1: Does exercise potentiate the effect of treatment?

Recently, glucagon-like peptide-1(GLP-1) receptor agonists have become a cornerstone for the treatment of obese patients with type 2 diabetes(T2D), exhibiting favorable effects on the cardiovascular outcome. In T2D, impaired GLP-1 secretion/function is observed, and gut microbiota dysbiosis is related to the GLP-1 resistance. Prior research has revealed that exercise increases GLP-1 levels in healthy and obese individuals; however, the efficacy of exercise on GLP-1 levels in patients with T2D remains unclear. Exercise may improve GLP-1 resistance rather than GLP-1 secretion in patients with T2D. Exercise increases the gut microbiota diversity, which could contribute to improving the GLP-1 resistance of T2D. Furthermore, the gut microbiota may play a role in the correlation between exercise and GLP-1. The combination of exercise and GLP-1-based therapy may have a synergistic effect on the treatment of T2D. Although the underlying mechanism remains unknown, exercise potentiates the efficacy of GLP-1 receptor agonist treatment in patients with T2D.

Effects of Dragon Boat Training on Cytokine Production and Oxidative Stress in Breast Cancer Patients: A Pilot Study

Regular exercise improves physical function and quality of life and reduces fatigue in cancer survivors;these health benefits could be due to the anti-inflammatory effects of exercise. In this study we examined the effects of a whole-body exercise programme and dragon boat paddling on the production of reactive oxygen species (ROMs), antioxidant capacity (BAP) and the circulating levels of several interleukins in breast cancer patients. Thirty four women surgically treated for breast cancer were enrolled in this study: 20 of them usually row dragon boats recreationally while 14 were sedentary. The 16-week training programme consisted of resistance and aerobic exercise, with the addition of dragon boat paddling for the last 8 weeks. Analyses of ROMs, cytokines and BAP were performed before and after 16 weeks of training. Results show a significant decrease in the ROMs value and significantly increased the BAP, IL-6, IL-8 and IL-15 levels. Exercise increased the BAP, IL-6, IL-8 and IL-15 values in the N+ patients, whereas only IL-6 and IL-8 were higher in the N0 patients. We demonstrated that muscle-derived cytokines are released after a training program and that the resulting decreased oxidative stress conditions underline the health-benefiting effects of such activity on breast cancer patients.

Skeletal muscle as an endocrine organ:Role of[Na+]i/[K+]i-mediated excitation-transcription coupling

During the last two decadesnumerous research teams demonstratedthat skeletalmuscles function as an exercise-dependent endocrine organ secreting dozens of myokines.Variety of physiological and pathophysiological implications of skeletalmusclemyokines secretion has been described;however,upstream signals and sensing mechanisms underlying this phenomenon remain poorly understood.It is well documented that in skeletal muscles intensive exercise triggers dissipation of transmembrane gradient of monovalent cations caused by permanent activation of voltage-gated Nat and Kt channels.Recently,we demonstrated that sustained elevation of the[Nat]i/[Kt]i ratio triggers expression of dozens ubiquitous genes including several canonical myokines,such as interleukin-6 and cyclooxygenase 2,in the presence of intra-and extracellular Ca2t chelators.These data allowed us to suggest a novel[Nat]i/[Kt]i-sensitive,Ca2t i-independent mechanism of excitation-transcription coupling which triggers myokine production.This pathway exists in parallel with canonical signaling mediated by Ca2t i,AMP-activated protein kinase and hypoxia-inducible factor 1a(HIF-1a).In ourmini-reviewwe briefly summarize data supporting this hypothesis as well as unresolved issues aiming to forthcoming studies.

Inflammation,physical activity,and chronic disease:An evolutionary perspective

Low-grade inflammation is emerging as a common feature of contemporary metabolic,psychiatric,and neurodegenerative diseases.Both physical inactivity and abdominal adiposity are associated with persistent systemic low-grade inflammation.Thus,the behavioral,biological,and physiological changes that cause a predisposition to obesity and other co-morbidities could have epigenetic underpinnings in addition to various evolutionary scenarios.A key assumption involves the potential for a mismatch between the human genome molded over generations,and the issue of adapting to the modern high calorie diet and common built environments promoting inactivity.This biological mismatch appears to have dire health consequences.Therefore,the goal of this article is to provide a brief overview on the importance of inflammation as part of human survival and how physical activity(PA)and physical inactivity are critical regulators of systemic inflammation.The review will highlight antiinflammatory effects of PA and exercise training from a metabolic and systemic signaling perspective,which includes skeletal muscle to utilization of fatty acids,TLR4 signaling,and myokine/adipokine effects.The available evidence suggests that PA,regular exercise,and weight loss offer both protection against and treatment for a wide variety of chronic diseases associated with low-grade inflammation through an improved inflammatory profile.

Roles of FGF21 and irisin in obesity-related diabetes and pancreatic diseases

In the past decades,skeletal muscle has become the focus of numerous studies due to its potential physiological role as an endocrine organ secreting hundreds of myokines.Among these myokines,fibroblast growth factor 21(FGF21)and irisin are novel hormone polypeptides sending signals to regulate the function of specific organs,like skeletal muscle,liver,pancreas,and adipose tissue.Both hormones have been reported to normalize glucose,improve insulin resistance,and promote lipid homeostasis,thereby preventing the development of metabolic disorders,such as obesity and diabetes.Besides preserving pancreaticβ-cell functions,FGF21 also protects pancreatic acini from inflammation and reduces proteotoxic stress via facilitating digestive enzyme secretion.Meanwhile,irisin is found to inhibit the pancreatic cancer cell growth as well.This review attempts to focus on the current knowledge of FGF21 and irisin and their effective roles in pancreas including pancreaticβ-and acinar cells under various physiological conditions,its anti-diabetic actions,and the clinical implications.