A feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21.

The cJun NH2-terminal kinase (JNK) signaling pathway is activated by metabolic stress and promotes the development of metabolic syndrome, including hyperglycemia, hyperlipidemia, and insulin resistance. This integrated physiological response involves cross-talk between different organs. Here we demonstrate that JNK signaling in adipocytes causes an increased circulating concentration of the hepatokine fibroblast growth factor 21 (FGF21) that regulates systemic metabolism. The mechanism of organ crosstalk is mediated by a feed-forward regulatory loop caused by JNK-regulated FGF21 autocrine signaling in adipocytes that promotes increased expression of the adipokine adiponectin and subsequent hepatic expression of the hormone FGF21. The mechanism of organ cross-talk places circulating adiponectin downstream of autocrine FGF21 expressed by adipocytes and upstream of endocrine FGF21 expressed by hepatocytes. This regulatory loop represents a novel signaling paradigm that connects autocrine and endocrine signaling modes of the same hormone in different tissues.

Lifelong LUTS: Understanding the bladder's role and implications across transition phases, a comprehensive review.

INTRODUCTION: Lower urinary tract symptoms (LUTSs) are a diverse array of urinary and pelvic dysfunctions that can emerge from childhood, extend through adulthood, and persist into older age. This narrative review aims to provide a comprehensive perspective on the continuum of LUTS and shed light on the underlying mechanisms and clinical implications that span across the lower urinary tract. METHODS: A panel of five experts from Belgium, the Netherlands, India, Denmark, and the United States participated in an intensive research to explore and pinpoint existing insights into the lifelong concept of LUTS, particularly at the pelvic level. The experts reviewed the existing literature and held a webinar to discuss their findings. RESULTS: Childhood LUTS can persist, resolve, or progress into bladder underactivity, dysfunctional voiding, or pain syndromes. The Lifelong character can be explained by pelvic organ cross-talk facilitated through complex neurological and nonneurological interactions. At the molecular level, the role of vasopressin receptors in the bladder's modulation and their potential relevance to therapeutic strategies for LUTS are explored. Frailty emerges as a parallel concept to lifelong LUTS, with a complex and synergistic relationship. Frailty, not solely an age-related condition, accentuates LUTS severity with insufficient evidence regarding the effectiveness and safety profile of the available therapeutic modalities. CONCLUSION: Understanding lifelong LUTSs offers insights into genetic, anatomical, neurological, and molecular mechanisms. Further research could identify predictive biomarkers, elucidate the role of clinically translatable elements in pelvic cross-talk, and uncover molecular signatures for personalized management.

IL-6 mediates the hepatic acute phase response after prerenal azotemia in a clinically defined murine model.

Prerenal azotemia (PRA) is a major cause of acute kidney injury and uncommonly studied in preclinical models. We sought to develop and characterize a novel model of PRA that meets the clinical definition: acute loss of glomerular filtration rate (GFR) that returns to baseline with resuscitation. Adult male C57BL/6J wild-type (WT) and IL-6-/- mice were studied. Intraperitoneal furosemide (4 mg) or vehicle was administered at time = 0 and 3 h to induce PRA from volume loss. Resuscitation began at 6 h with 1 mL intraperitoneal saline for four times for 36 h. Six hours after furosemide administration, measured glomerular filtration rate was 25% of baseline and returned to baseline after saline resuscitation at 48 h. After 6 h of PRA, plasma interleukin (IL)-6 was significantly increased, kidney and liver histology were normal, kidney and liver lactate were normal, and kidney injury molecule-1 immunofluorescence was negative. There were 327 differentially regulated genes upregulated in the liver, and the acute phase response was the most significantly upregulated pathway; 84 of the upregulated genes (25%) were suppressed in IL-6-/- mice, and the acute phase response was the most significantly suppressed pathway. Significantly upregulated genes and their proteins were also investigated and included serum amyloid A2, serum amyloid A1, lipocalin 2, chemokine (C-X-C motif) ligand 1, and haptoglobin; hepatic gene expression and plasma protein levels were all increased in wild-type PRA and were all reduced in IL-6-/- PRA. This work demonstrates previously unknown systemic effects of PRA that includes IL-6-mediated upregulation of the hepatic acute phase response.NEW & NOTEWORTHY Prerenal azotemia (PRA) accounts for a third of acute kidney injury (AKI) cases yet is rarely studied in preclinical models. We developed a clinically defined murine model of prerenal azotemia characterized by a 75% decrease in measured glomerular filtration rate (GFR), return of measured glomerular filtration rate to baseline with resuscitation, and absent tubular injury. Numerous systemic effects were observed, such as increased plasma interleukin-6 (IL-6) and upregulation of the hepatic acute phase response.

Nerve-macrophage interactions in cardiovascular disease.

The heart is highly innervated by autonomic neurons, and dynamic autonomic regulation of the heart and blood vessels is essential for animals to carry out the normal activities of life. Cardiovascular diseases, including heart failure and myocardial infarction, are characterized in part by an imbalance in autonomic nervous system activation, with excess sympathetic and diminished parasympathetic activation. Notably, however, this is often accompanied by chronic inflammation within the cardiovascular tissues, which suggests there are interactions between autonomic dysregulation and inflammation. Recent studies have been unraveling the mechanistic links between autonomic nerves and immune cells within the cardiovascular system. The autonomic nervous system and immune system also act in concert to coordinate the actions of multiple organs that not only maintain homeostasis but also likely play key roles in disease-disease interactions, such as cardiorenal syndrome and multimorbidity. In this review, we summarize the physiological and pathological interactions between autonomic nerves and macrophages in the context of cardiovascular disease.

Mechanisms by Which Skeletal Muscle Myokines Ameliorate Insulin Resistance.

The skeletal muscle is the largest organ in the body and secretes circulating factors, including myokines, which are involved in various cellular signaling processes. Skeletal muscle is vital for metabolism and physiology and plays a crucial role in insulin-mediated glucose disposal. Myokines have autocrine, paracrine, and endocrine functions, serving as critical regulators of myogenic differentiation, fiber-type switching, and maintaining muscle mass. Myokines have profound effects on energy metabolism and inflammation, contributing to the pathophysiology of type 2 diabetes (T2D) and other metabolic diseases. Myokines have been shown to increase insulin sensitivity, thereby improving glucose disposal and regulating glucose and lipid metabolism. Many myokines have now been identified, and research on myokine signaling mechanisms and functions is rapidly emerging. This review summarizes the current state of the field regarding the role of myokines in tissue cross-talk, including their molecular mechanisms, and their potential as therapeutic targets for T2D.

Unraveling the Transcriptional Dynamics of NASH Pathogenesis Affecting Atherosclerosis.

The prevalence of non-alcoholic steatohepatitis (NASH) is rapidly increasing and associated with cardiovascular disease (CVD), the major cause of mortality in NASH patients. Although sharing common risk factors, the mechanisms by which NASH may directly contribute to the development to CVD remain poorly understood. The aim of this study is to gain insight into key molecular processes of NASH that drive atherosclerosis development. Thereto, a time-course study was performed in Ldlr-/-.Leiden mice fed a high-fat diet to induce NASH and atherosclerosis. The effects on NASH and atherosclerosis were assessed and transcriptome analysis was performed. Ldlr-/-.Leiden mice developed obesity, hyperlipidemia and insulin resistance, with steatosis and hepatic inflammation preceding atherosclerosis development. Transcriptome analysis revealed a time-dependent increase in pathways related to NASH and fibrosis followed by an increase in pro-atherogenic processes in the aorta. Gene regulatory network analysis identified specific liver regulators related to lipid metabolism (SC5D, LCAT and HMGCR), inflammation (IL1A) and fibrosis (PDGF, COL3A1), linked to a set of aorta target genes related to vascular inflammation (TNFA) and atherosclerosis signaling (CCL2 and FDFT1). The present study reveals pathogenic liver processes that precede atherosclerosis development and identifies hepatic key regulators driving the atherogenic pathways and regulators in the aorta.

Lung metabolomics after ischemic acute kidney injury reveals increased oxidative stress, altered energy production, and ATP depletion.

Acute kidney injury (AKI) is a complex disease associated with increased mortality that may be due to deleterious distant organ effects. AKI associated with respiratory complications, in particular, has a poor outcome. In murine models, AKI is characterized by increased circulating cytokines, lung chemokine upregulation, and neutrophilic infiltration, similar to other causes of indirect acute lung injury (ALI; e.g., sepsis). Many causes of lung inflammation are associated with a lung metabolic profile characterized by increased oxidative stress, a shift toward the use of other forms of energy production, and/or a depleted energy state. To our knowledge, there are no studies that have evaluated pulmonary energy production and metabolism after AKI. We hypothesized that based on the parallels between inflammatory acute lung injury and AKI-mediated lung injury, a similar metabolic profile would be observed. Lung metabolomics and ATP levels were assessed 4 h, 24 h, and 7 days after ischemic AKI in mice. Numerous novel findings regarding the effect of AKI on the lung were observed including 1) increased oxidative stress, 2) a shift toward alternate methods of energy production, and 3) depleted levels of ATP. The findings in this report bring to light novel characteristics of AKI-mediated lung injury and provide new leads into the mechanisms by which AKI in patients predisposes to pulmonary complications.

Importance of breath tests for the evaluation liver function in patients with chronic kidney disease.

Breath tests for the evaluation liver metabolic function are a non-invasive diagnostic method with high sensitivity and specificity. Up today, the issue of liver damage in patients with chronic kidney disease has not been investigated sufficiently, although it might have significant clinical consequences. The following article describes the principles of breath tests, experiences with breath tests in patients with chronic kidney disease (CKD) and the results of our pilot study with methacetin breath tests in patients with CKD and in regular peritoneal dialysis treatment.

Do skeletal muscle-secreted factors influence the function of pancreatic ß-cells?

Skeletal muscle is an endocrine organ that secretes a variety of compounds including proteins (myokines), metabolites, microRNAs (miRNAs), and exosomes, many of which are regulated by exercise and play important roles in endocrine signaling. Interorgan communication via muscle-secreted factors therefore provides a novel area for investigation and implicates the importance of skeletal muscle in the pathophysiology of metabolic diseases such as type 2 diabetes (T2D). Given that underlying molecular mechanisms of T2D are subject of ongoing research, in light of new evidence it is probable that interorgan cross-talk between skeletal muscle and pancreatic ß-cells plays an important part. To date, the number of studies published in this field provide the basis of this review. Specifically, we discuss current experimental evidence in support for a role of skeletal muscle to ß-cell cross-talk, paying particular attention to muscle-secreted factors including myokines, metabolites, miRNAs, and factors contained within exosomes that influence the function and/or the survival of ß-cells in health and disease. In reviewing this evidence, we provide an update on the list of known muscle-secreted factors that have potential to influence the function and/or survival of ß-cells under normal and diabetic conditions. We also report limitations of current cross-talk methods and discuss future directions in this growing field.

Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue.

In most clinical trials, thiazolidinediones do not show any relevant anti-cancer activity when used as mono-therapy. Clinical inefficacy contrasts ambiguous pre-clinical data either favoring anti-tumor activity or tumor promotion. However, if thiazolidinediones are combined with additional regulatory active drugs, so-called 'master modulators' of tumors, i.e., transcriptional modulators, metronomic low-dose chemotherapy, epigenetically modifying agents, protein binding pro-anakoinotic drugs, such as COX-2 inhibitors, IMiDs, etc., the results indicate clinically relevant communicative reprogramming of tumor tissues, i.e., anakoinosis, meaning 'communication' in ancient Greek. The concerted activity of master modulators may multifaceted diversify palliative care or even induce continuous complete remission in refractory metastatic tumor disease and hematologic neoplasia by establishing novel communicative behavior of tumor tissue, the hosting organ, and organism. Re-modulation of gene expression, for example, the up-regulation of tumor suppressor genes, may recover differentiation, apoptosis competence, and leads to cancer control-in contrast to an immediate, 'poisoning' with maximal tolerable doses of targeted/cytotoxic therapies. The key for uncovering the therapeutic potential of Peroxisome proliferator-activated receptor γ (PPARγ) agonists is selecting the appropriate combination of master modulators for inducing anakoinosis: Now, anakoinosis is trend setting by establishing a novel therapeutic pillar while overcoming classic obstacles of targeted therapies, such as therapy resistance and (molecular-)genetic tumor heterogeneity.

Fabry's disease: an example of cardiorenal syndrome type 5.

Cardiorenal syndrome type 5 (CRS-5) includes conditions where there is a simultaneous involvement of the heart and kidney from a systemic disorder. This is a bilateral organ cross talk. Fabry's disease (FD) is a devastating progressive inborn error of metabolism with lysosomal glycosphingolipid deposition in variety of cell types, capillary endothelial cells, renal, cardiac and nerve cells. Basic effect is absent or deficient activity of lysosomal exoglycohydrolase a-galactosidase A. Renal involvement consists of proteinuria, isosthenuria, altered tubular function, presenting in second or third decade leading to azotemia and end-stage renal disease in third to fifth decade mainly due to irreversible changes to glomerular, tubular and vascular structures, especially highlighted by podocytes foot process effacement. Cardiac involvement consists of left ventricular hypertrophy, right ventricular hypertrophy, arrhythmias (sinus node and conduction system impairment), diastolic dysfunction, myocardial ischemia, infarction, transmural replacement fibrosis, congestive heart failure and cardiac death. Management of FD is based on enzymatic replacement therapy and control of renal (with anti-proteinuric agents such as angiotensin-converting enzyme inhibitors-and/or angiotensin II receptor blockers), brain (coated aspirin, clopidogrel and statin to prevent strokes) and heart complications (calcium channel blockers for ischemic cardiomyopathy, warfarin and amiodarone or cardioverter device for arrhythmias).

Leveraging inter-individual transcriptional correlation structure to infer discrete signaling mechanisms across metabolic tissues.

Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by 'brute force' surveys of all genes within RNA-sequencing measures across tissues within a population. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or high-fat/high-sucrose (HFHS) diet. Variation of genes such as FGF21, ADIPOQ, GCG, and IL6 showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liver PCSK9) and genes encoding enzymes producing metabolites (adipose PNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource as gene-derived correlations across tissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways, and network architectures across metabolic organs.

Netrin-1 regulates colon-kidney cross talk through suppression of IL-6 function in a mouse model of DSS-colitis.

Organ cross talk is increasingly appreciated in human disease, and inflammatory mediators are shown to mediate distant organ injury in many disease models. Colitis and intestinal injury are known to be mediated by infiltrating immune cells and their secreted cytokines. However, its effect on other organs, such as the kidney, has never been studied. In the current study, we examined the effect of dextran sulfate sodium (DSS)-colitis on kidney injury and inflammation. In addition, we hypothesized that netrin-1 could modulate colon-kidney cross talk through regulation of inflammation and apoptosis. Consistent with our hypothesis, DSS-colitis induced acute kidney injury in mice. Epithelial-specific overexpression of netrin-1 suppressed both colitis and colitis-induced acute kidney injury, which was associated with reduced weight loss, neutrophil infiltration into colon mucosa, intestinal permeability, epithelial cell apoptosis, and cytokine and chemokine production in netrin-1 transgenic mice colon and kidney. To determine whether netrin-1-protective effects were mediated through suppression of IL-6, IL-6 knockout mice were treated with DSS and acute kidney injury was determined. IL-6 knockout was resistant to colitis and acute kidney injury. Moreover, administration of IL-6 to netrin-1 transgenic mice did not affect the netrin-1-protective effects on the colon and kidney, suggesting that netrin-1 may reduce both IL-6 production and its activity. The present study identifies previously unrecognized cross talk between the colon and kidney, and netrin-1 may limit distant organ injury by suppressing inflammatory mediators and apoptosis.

The liver-derived exosomes stimulate insulin gene expression in pancreatic beta cells under condition of insulin resistance.

Introduction: An insufficient functional beta cell mass is a core pathological hallmark of type 2 diabetes (T2D). Despite the availability of several effective pharmaceuticals for diabetes management, there is an urgent need for novel medications to protect pancreatic beta cells under diabetic conditions. Integrative organ cross-communication controls the energy balance and glucose homeostasis. The liver and pancreatic islets have dynamic cross-communications where the liver can trigger a compensatory beta cell mass expansion and enhanced hormonal secretion in insulin-resistant conditions. However, the indispensable element(s) that foster beta cell proliferation and insulin secretion have yet to be completely identified. Exosomes are important extracellular vehicles (EVs) released by most cell types that transfer biological signal(s), including metabolic messengers such as miRNA and peptides, between cells and organs. Methods: We investigated whether beta cells can take up liver-derived exosomes and examined their impact on beta cell functional genes and insulin expression. Exosomes isolated from human liver HepG2 cells were characterized using various methods, including Transmission Electron Microscopy (TEM), dynamic light scattering (DLS), and Western blot analysis of exosomal markers. Exosome labeling and cell uptake were assessed using CM-Dil dye. The effect of liver cell-derived exosomes on Min6 beta cells was determined through gene expression analyses of beta cell markers and insulin using qPCR, as well as Akt signaling using Western blotting. Results: Treatment of Min6 beta cells with exosomes isolated from human liver HepG2 cells treated with insulin receptor antagonist S961 significantly increased the expression of beta cell markers Pdx1, NeuroD1, and Ins1 compared to the exosomes isolated from untreated cells. In line with this, the activity of AKT kinase, an integral component of the insulin receptor pathway, is elevated in pancreatic beta cells, as represented by an increase in AKT's downstream substrate, FoxO1 phosphorylation. Discussions: This study suggests that liver-derived exosomes may carry a specific molecular cargo that can affect insulin expression in pancreatic beta cells, ultimately affecting glucose homeostasis.

Lung-brain 'cross-talk': systemic propagation of cytokines in the ARDS via the bloodstream using a blood transfusion model does not influence cerebral inflammatory response in pigs.

Background: Interorgan cross-talk describes the phenomenon in which a primarily injured organ causes secondary damage to a distant organ. This cross-talk is well known between the lung and brain. One theory suggests that the release and systemic distribution of cytokines via the bloodstream from the primarily affected organ sets in motion proinflammatory cascades in distant organs. In this study, we analysed the role of the systemic distribution of cytokines via the bloodstream in a porcine ARDS model for organ cross-talk and possible inflammatory changes in the brain. Methods: After approval of the State and Institutional Animal Care Committee, acute respiratory distress syndrome (ARDS) induction with oleic acid injection was performed in seven animals. Eight hours after ARDS induction, blood (35-40 ml kg-1) was taken from these seven 'ARDS donor' pigs. The collected 'ARDS donor' blood was transfused into seven healthy 'ARDS-recipient' pigs. Three animals served as a control group, and blood from these animals was transfused into three healthy pigs after an appropriate ventilation period. All animals were monitored for 8 h using advanced cardiorespiratory monitoring. Postmortem assessment included cerebral (hippocampal and cortex) mediators of early inflammatory response (IL-6, TNF-alpha, iNOS, sLCN-2), wet-to-dry ratio and lung histology. TNF-alpha serum concentration was measured in all groups. Results: ARDS was successfully induced in the 'ARDS donor' group, and serum TNF-alpha levels were elevated compared with the 'ARDS-recipient' group. In the 'ARDS-recipient' group, neither significant ARDS alterations nor upregulation of inflammatory mediators in the brain tissue were detected after high-volume random allogenic 'ARDS-blood' transfusion. The role of the systemic distribution of inflammatory cytokines from one affected organ to another could not be confirmed in this study.

Lipocalin 2 as a Putative Modulator of Local Inflammatory Processes in the Spinal Cord and Component of Organ Cross talk After Spinal Cord Injury.

Lipocalin 2 (LCN2), an immunomodulator, regulates various cellular processes such as iron transport and defense against bacterial infection. Under pathological conditions, LCN2 promotes neuroinflammation via the recruitment and activation of immune cells and glia, particularly microglia and astrocytes. Although it seems to have a negative influence on the functional outcome in spinal cord injury (SCI), the extent of its involvement in SCI and the underlying mechanisms are not yet fully known. In this study, using a SCI contusion mouse model, we first investigated the expression pattern of Lcn2 in different parts of the CNS (spinal cord and brain) and in the liver and its concentration in blood serum. Interestingly, we could note a significant increase in LCN2 throughout the whole spinal cord, in the brain, liver, and blood serum. This demonstrates the diversity of its possible sites of action in SCI. Furthermore, genetic deficiency of Lcn2 (Lcn2-/-) significantly reduced certain aspects of gliosis in the SCI-mice. Taken together, our studies provide first valuable hints, suggesting that LCN2 is involved in the local and systemic effects post SCI, and might modulate the impairment of different peripheral organs after injury.

Acute kidney injury in the critically ill: an updated review on pathophysiology and management.

Acute kidney injury (AKI) is now recognized as a heterogeneous syndrome that not only affects acute morbidity and mortality, but also a patient's long-term prognosis. In this narrative review, an update on various aspects of AKI in critically ill patients will be provided. Focus will be on prediction and early detection of AKI (e.g., the role of biomarkers to identify high-risk patients and the use of machine learning to predict AKI), aspects of pathophysiology and progress in the recognition of different phenotypes of AKI, as well as an update on nephrotoxicity and organ cross-talk. In addition, prevention of AKI (focusing on fluid management, kidney perfusion pressure, and the choice of vasopressor) and supportive treatment of AKI is discussed. Finally, post-AKI risk of long-term sequelae including incident or progression of chronic kidney disease, cardiovascular events and mortality, will be addressed.

The relationship between obstructive sleep apnea syndrome and obesity: A new perspective on the pathogenesis in terms of organ crosstalk.

INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is a common disorder that has a major impact on public health. The connection between OSAS and obesity is very complex and likely represents an interaction between biological and lifestyle factors. Oxidative stress, inflammation and metabolic dysregulation are both actors involved in the pathogenesis of OSAS and obesity. Also, the current evidence suggests that gut microbiota plays a significant role in the emergence and progression of some metabolic disorders. When the relationship between OSAS and obesity is evaluated extensively, it is understood that they show mutual causality with each other, and that metabolic challenges such as impaired microbiota affect this bidirectional organ interaction, and by ensuing organ injury. OBJECTIVES: The aim of this study is to investigate the association between OSAS and obesity, and the effect of "organ crosstalk" on the pathogenesis of the relationship and to contribute to the diagnosis and treatment options in the light of current data. DATA SOURCE: We performed an electronic database search including PubMed, EMBASE and Web of Science. We used the following search terms: OSAS, obesity, inflammation, metabolic dysregulation and gut microbiota. CONCLUSION: Obesity and OSAS adversely affect many organs and systems. Besides the factors affecting the diagnosis of the OSAS-obesity relationship, mutual organ interactions among the respiratory system, adipose tissue and intestines should not be ignored for prevention and treatment of OSAS and obesity. Comprehensive clinical trials addressing the efficacy and efficiency of current or potential treatments on therapeutic applications in the OSAS-obesity relationship are needed.

The JAK/STAT Pathway in Skeletal Muscle Pathophysiology.

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is a key intracellular mediator of a variety of metabolically relevant hormones and cytokines, including the interleukin-6 (IL-6) family of cytokines. The JAK/STAT pathway transmits extracellular signals to the nucleus, leading to the transcription of genes involved in multiple biological activities. The JAK/STAT pathway has been reported to be required for the homeostasis of different tissues and organs. Indeed, when deregulated, it promotes the initiation and progression of pathological conditions, including cancer, obesity, diabetes, and other metabolic diseases. In skeletal muscle, activation of the JAK/STAT pathway by the IL-6 cytokines accounts for opposite effects: on the one hand, it promotes muscle hypertrophy, by increasing the proliferation of satellite cells; on the other hand, it contributes to muscle wasting. The expression of IL-6 and of key members of the JAK/STAT pathway is regulated at the epigenetic level through histone methylation and histone acetylation mechanisms. Thus, manipulation of the JAK/STAT signaling pathway by specific inhibitors and/or drugs that modulate epigenetics is a promising therapeutic intervention for the treatment of numerous diseases. We focus this review on the JAK/STAT pathway functions in striated muscle pathophysiology and the potential role of IL-6 as an effector of the cross talk between skeletal muscle and other organs.