Layout 1 Thematic Section: Advances in Musculoskeletal and Neuromuscular Rehabilitation Eur J Transl Myol 35 (3) 13365, 2025 doi: 10.4081/ejtm.2025.13365 Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) is a type of chronic liver disease that has a prevalence rate of 38% worldwide.1 MASLD encompasses various liver disorders, ranging from a fat buildup in the liver (i.e., fatty liver) to inflammation and liver damage, known as non-alcoholic steatohepatitis.2 Genetic, environmental, and metabolic risk factors influence the development of MASLD.3,4 Among these, metabolic disorders, including insulin resistance, obesity, metabolic syndrome, and type 2 diabetes mellitus, are prominent lifestyle-related risk factors.5,6 This condition is characterized by excessive fat accumulation in hepatocytes, which triggers inflammation and oxidative stress. Over time, this process can lead to progressive liver damage, resulting in cirrhosis, liver failure, or even carcinoma. In addition to its effects on the liver, inflammation and ox- Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is a condition characterized by altered liver function due to fatty accumulation, which can lead to liver inflammation and, in advanced stages, liver carcinoma. MASLD is closely linked to several metabolic alterations, such as obesity and insulin resistance, which directly affect skeletal muscles and contribute to the development of sarcopenia. Sarcopenia is the loss of muscle mass and strength, leading to decreased physical performance in severe stages. Skeletal muscles secrete molecules known as myokines under various conditions, such as exercise or diseases like MASLD. These myokines modulate communication between the skeletal muscle and other tissues. These myokines regulate muscle mass and, in pathological conditions, contribute to the development of sarcopenia. Emerging evidence highlights the crucial role of myokines in regulating skeletal muscle metabolism and function in MASLD. Myokines influence muscle metabolism, inflammation, and insulin sensitivity, offering potential therapeutic targets for managing muscle atrophy and sarcopenia in the context of MASLD. Understanding the interaction between myokines and skeletal muscle may lead to novel interventions to mitigate MASLD progression and sarcopenia. This review examines the mechanisms by which myokines regulate skeletal muscle metabolism and function in the context of MASLD. Key Words: metabolic dysfunction-associated steatotic liver disease, sarcopenia, myokines. Eur J Transl Myol 35 (3) 13365, 2025 doi: 10.4081/ejtm.2025.13365 Impact of myokines on chronic liver diseases: exploring the effects of metabolic dysfunction-associated steatotic liver disease (MASLD) on skeletal muscle. A narrative review Francisco Aguirre,1,2,3 Mayalen Valero-Breton,1,2,3 Daniel Cabrera,4,5 Luis Peñailillo,6 María Carolina Otero,7 Claudia Fredes,8 Claudio Cabello-Verrugio1,2,3 1Center for Research on Pandemic Resilience, Faculty of Life Sciences and Institute of Public Health, Universidad Andres Bello, Santiago, Chile; 2Laboratory of Muscle Pathology, Fragility and Aging, Department of Biological Sciences, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile; 3Millennium Institute on Immunology and Immunotherapy, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile; 4Center for Biomedical Research and Innovation (CiiB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile; 5Facultad de Ciencias de la Salud, Escuela de Kinesiología, Universidad Bernardo O Higgins, Santiago, Chile; 6Exercise and Rehabilitation Sciences Institute, School of Physical Therapy, Faculty of Rehabilitation Sciences, Universidad Andrés Bello, Santiago, Chile; 7Escuela de Química y Farmacia, Facultad de Medicina, Universidad Andres Bello, Santiago, Chile; 8Exercise and Rehabilitation Sciences Institute, Postgraduate, Faculty of Rehabilitation Sciences, Universidad Andres Bello, Santiago, Chile. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (CC BY-NC 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. - 277 - Impact of myokines on chronic liver diseases Eur J Transl Myol 35 (3) 13365, 2025 doi: 10.4081/ejtm.2025.13365 idative stress produced by hepatocytes associated with MASLD extend to other tissues, such as the endothelium, peripheral nerves, heart, and skeletal muscles.7 Skeletal muscle plays a crucial role in glucose uptake and whole- body metabolism, as it accounts for approximately 50% of body mass. Due to Insulin Resistance (IR) observed in MASLD, decreased muscle protein synthesis results from impaired insulin-dependent signaling. Moreover, IR can in- crease protein degradation, reducing muscle mass.8 This de- cline in muscle mass has been associated with muscle weakness and the development of sarcopenia, typical fea- tures of patients with MASLD.9,10 Sarcopenia is a skeletal muscle syndrome characterized by decreased muscle strength, mass, and physical performance, which can be secondarily developed due to pathological conditions, such as MASLD.11,12 Sarcopenia has also been described by in- creased degradation and/or decreased synthesis of sarcome- ric proteins, mitochondrial dysfunction, and oxidative stress in skeletal muscle.7,13,14 Some studies suggest that in MASLD, sarcopenia has been associated with an increased inflammatory state, which re- sults in the release of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF- α), as well as other soluble molecules into the bloodstream, such as bile acids and ammonia. In addition, reduced plasma levels of insulin-like growth factor 1 (IGF-1), an anabolic factor in skeletal muscle, have also been reported in MASLD.15 These circulating molecules have been shown to modulate muscle mass loss and contribute to the devel- opment of sarcopenia.10,11,16 In recent years, it has been described that skeletal muscle communicates with other tissues and organs, including the liver, adipose tissue, brain, and bone, by secretion of soluble molecules known as myokines.17 Myokines exert autocrine, paracrine, and endocrine actions to regulate metabolic pro- cesses such as glucose uptake, lipid oxidation, and energy production.18 It has been shown that MASLD modulates myokine secretion, which regulates muscle mass and the development of sarcopenia.19,21 This review outlines the main effects of MASLD on myokine secretion and its mus- cular and systemic consequences. Myokines regulate the metabolism and functions of the skeletal muscle in MASLD Recent studies emphasize the essential role of myokines in regulating skeletal muscle characteristics and function. Myokines impact muscle metabolism, inflammation, and insulin sensitivity, which are expected consequences of MASLD. By elucidating the relationship between myo- kines and skeletal muscle, novel therapeutic strategies for managing MASLD can be discovered. This review will dis- cuss the evidence of the most reported myokines in the lit- erature, which include Myostatin, IL-6, IGF-1, IL-15, Irisin, LIF, FGF21, and Myonectin. Myostatin Myostatin, also known as growth differentiation factor 8 (GDF8), is a myokine belonging to the transforming growth factor-beta (TGF-β) superfamily of cytokines.22 This myokine is expressed in cardiac and adipose tissue but is most abundant in skeletal muscle.23 Myostatin is a negative regulator of muscle mass, and its absence in- creases muscle mass, contributing to hypertrophy.24 Skele- tal muscle cells synthesize pre-myostatin, which comprises an N-terminal pro-domain region, a biolog- ically active C-terminal domain, and an N-terminal signal sequence. Proteolytic cleavage is required to activate it.25 Myostatin acts on skeletal muscle to bind to the activin type II receptor B (ActRIIB), which activates the Smad signaling pathway, triggering the phosphorylation of Smad2/3 and forming a complex with Smad4.23 This ac- tivated complex translocates into the nucleus, blocking the critical activity of myogenic regulator factors (MRF), in- cluding myoblast determination protein 1 (MyoD), myo- cyte-specific enhancer factor (MEF2), Myogenic factor 5 (Myf5), and myogenin.26 This blockage halts the myoblast proliferation and differentiation, leading to the failure of the myogenic process. Also, myostatin activates the Fork- head box protein O1 (FoxO1), a transcriptional factor in- volved in the activation of protein degradation pathways, such as the Ubiquitin-Proteasome System (UPS), by in- creasing the expression of the E3-ligases MuRF-1 and atrogin-1.27 On the other hand, myostatin inhibits muscle hypertrophy by downregulating the activity of the Akt/mTOR pathway, which is involved in protein synthe- sis.23,25,28 Under physiological conditions, myostatin is present in low concentrations in the bloodstream and skeletal muscle. Ho- wever, chronic diseases (such as cancer), inflammatory con- ditions, sarcopenia, immobilization, bed rest, and traumatic musculoskeletal injury increase myostatin levels in muscle and serum.2 Interestingly, myostatin expression decreases after acute and chronic endurance and resistance exercises in rodents and humans (compared to most myokines de- scribed to date).29,30 Regarding MASLD, the serum levels of myostatin are in- creased due to hyperammonemia developed in the late stage of the disease.31 This increment of myostatin is me- diated by skeletal muscle through an NF-κB-dependent mechanism.31-33 The elevated levels of myostatin induced by hyperammonemia decrease muscle mass due to the ac- tivation of the degradation mechanisms such as UPS and autophagy, which depend on NF-κB and FoxO.26,34,35 The increase of myostatin in metabolic diseases has also been correlated with IR due to the downregulated expression of GLUT4 and the decreased phosphorylation of IRS1.36 In the same direction, the absence of myostatin in KO mice improves IR and increases muscle mass in liver dis- eases.37 Several strategies have been developed to inhibit myostatin expression or block its activity, improving mus- cle mass and metabolic functions in animal models.38 Thus, blocking antibodies for myostatin or its receptors ActIIB or ActIIA have beneficial effects for treating mus- cle weakness in different diseases such as Duchenne mus- cular dystrophy (in the mdx model) or sarcopenia derived from chronic kidney disease or cancer, among others.39-41 Specifically, follistatin, a soluble inhibitor of myostatin that competes for the binding to ActRIIA, which is in- - 278 - Impact of myokines on chronic liver diseases Eur J Transl Myol 35 (3) 13365, 2025 doi: 10.4081/ejtm.2025.13365 creased during exercise, positively affects muscle mass, inducing hypertrophy.42-44 In summary, increased myostatin levels observed under pathological conditions such as MASLD contribute to mus- cle wasting and sarcopenia (Figure 1), highlighting its po- tential as a therapeutic target for muscle-related disorders. Interleukin 6 (IL-6) IL-6 is a pro-inflammatory cytokine synthesized by several cell types, including activated monocytes/macrophages, vascular endothelial cells, fibroblasts, and skeletal muscle. It is crucial in triggering the acute phase reaction in the in- flammatory process.28 Under physiological conditions, cir- culating IL-6 levels are low but can increase more than 1,000-fold during an inflammatory state.45 Beyond its role in inflammation, IL-6 is also crucial in metabolism by con- trolling body weight, liver physiology, and bone metabo- lism.45 Within skeletal muscle, IL-6 can exhibit both pro-inflammatory and anti-inflammatory properties de- pending on the context. The pro-inflammatory actions of IL-6 are particularly evident during chronic inflammation, such as a response to an injury (i.e., muscle damage).46 Under these circumstances, elevated levels of TNF-α and IL-1β further amplify IL-6 production, which inhibits insu- lin activity, promotes IR, and could be a predictor for type 2 diabetes mellitus.47 This pro-inflammatory function oc- curs through an increase in STAT3 activation, inhibiting PI3K-akt signaling, decreasing protein synthesis, and in- creasing myostatin expression, thereby contributing to the development of sarcopenia.45,48 The anti-inflammatory role of IL-6 is observed in response - 279 - Figure 1. Actions of myokines in healthy and pathological (MASLD) conditions. In MASLD, skeletal muscle releases myokines that promote liver dysfunction by altering glucose and lipid metabolism. These events produce insulin resistance and sarcopenia in the SM by increasing myostatin and IL-6 levels. Meanwhile, other myokines decrease their secretion in this condition, reinforcing sarcopenia and the metabolic disorders in skeletal muscle and liver (decreased irisin, IGF-1, and IL-15 levels). In healthy subjects, the exercise causes the release of myokines from the skeletal muscle producing an anti-inflammatory effect (increased IL-6 levels), metabolic control of glucose, insulin, and triglyceride levels, and muscle hypertrophy (increased irisin, IGF-1 and IL-15, and decreased myostatin levels). MASLD, metabolic dysfunction-associated steatotic liver disease; SM, skeletal muscle; IL, interleukin; IGF-1, insulin-like growth factor-1. Impact of myokines on chronic liver diseases Eur J Transl Myol 35 (3) 13365, 2025 doi: 10.4081/ejtm.2025.13365 to muscle contraction in the absence of muscle injury.49 During and following exercise, an acute increase in IL-6 is observed as a direct response to muscle contraction.21,50 The peak concentration of IL-6 depends on the intensity of the exercise. During exercise, IL-6 positively affects various organs and tissues, improving glucose sensitivity and optimizing metabolism to provide energy substrates for muscle contraction.51,52 IL-6 mediates its effects through interaction with its primary receptor (IL6Rα) and a secondary receptor (gp130), which activates several sig- naling pathways, including ERK1/2 MAPK, PI3K, Akt, and AMPK. This activation promotes increased glucose uptake and fatty acid oxidation.46,50 In MASLD patients, the severity of the condition is directly proportional to the increase in IL-6 levels.53 Moreover, el- evated IL-6 levels in MASLD are related to adverse effects, such as enhanced liver susceptibility to injury, inflamma- tion, and even increased risk of liver cancer.54 IL-6 activates STAT3, a lipogenic factor in hepatocytes, leading to hepatic steatosis in MASLD.55 This, in turn, exacerbates NF-κB ac- tivity, which is also stimulated by IL-6. Elevated IL-6 levels mediate inflammation by recruiting Kupffer cells and con- tribute to IR through up-regulation of the suppressor cyto- kine signaling 3 (SOCS3).56 In muscle tissue, IL-6 plays a pivotal role in IR and contributes to systemic low-grade in- flammation, thereby aggravating the metabolic disorders associated with the disease.45,52 Thus, in chronic conditions such as MASLD, persistently elevated levels of IL-6 in the bloodstream increase the ac- tivity of catabolic pathways while decreasing anabolic path- ways in skeletal muscle, thereby promoting the development of sarcopenia (Figure 1). Insulin-like growth factor-1 (IGF-1) IGF-1 is a growth factor that is also considered myokine. It consists of a single-chain polypeptide of 70 amino acids, cross-linked by three disulfide bridges, with a molecular weight of 7 kDa.57 IGF-1 is mainly synthesized and secreted by the liver and skeletal muscles, exerting its functions on various target tissues in an endocrine, paracrine, and auto- crine manner. Endurance and resistance training can in- crease IGF-1 levels in skeletal muscles, promoting cell growth and differentiation by stimulating anabolic path- ways and decreasing catabolic pathways activity.57,58 Spe- cifically, IGF-1 binds to the IGF-1 receptor (IGF-1R), activates it by phosphorylation, and leads to activation of the AMPK/ERK and Akt/mTOR axes. This activation in- creases muscle protein synthesis and is expected to increase muscle mass.59 Patients with MASLD exhibit low serum levels of IGF-1 due to the severity of inflammation, hepatocyte ballooning, and liver fibrosis.60,61 Under normal conditions, IGF-1 helps prevent IR, mitochondrial dysfunction, triglyceride ac- cumulation, inflammation, and oxidative stress.62 Con- sequently, reduced IGF-1 levels in NALD patients may exacerbate these events, activating hepatic stellate cells to produce more Extracellular Matrix (ECM) and leading to fibrogenesis and cirrhosis.63 In MASLD-induced sarcopenia, there is a direct correla- tion between reduced muscle mass and strength and de- creased circulating IGF-1 levels.16 This indicates that a de- cline in IGF-1 secretion could contribute to the devel- opment of sarcopenia in MASLD. Similarly, patients with obesity, often associated with fatty liver and MASLD, present a decreased expression of IGF-1 in skeletal mus- cle, leading to an imbalance in the IGF-1 axis and an in- creased risk of developing sarcopenia.64 Interestingly, it should be noted that in cases of chronic liver disease, treat- ment with lithocholic acid has been shown to enhance IGF-1 signaling, improving protein synthesis and muscle mass.65 Thus, IGF-1 is a myokine associated with increased muscle mass and is secreted by skeletal muscle in response to ex- ercise. A dysregulated IGF-1 axis can disrupt muscle mass regulation by increasing protein catabolism and reducing the activity of anabolism pathways, thereby inducing sar- copenia. In MASLD, the IGF-1 levels are low, which could contribute to the development of sarcopenia, a common symptom of liver disease (Figure 1). Interleukin-15 (IL-15) IL-15 is a 14 kDa myokine expressed and secreted in sev- eral non-lymphoid tissues, including the heart, lungs, and brain. In skeletal muscle, IL-15 is secreted in response to endurance or resistance exercise, depending more on the duration and intensity of the training than on its type.66,67 IL-15 interacts with the IL-15 receptor alpha (IL-15Rα) and enhances the activity of peroxisome proliferator-activated receptor gamma (PPAR-g) and transcriptional co-activator peroxisome proliferator-activated receptor-gamma co-acti- vator 1-alpha (PGC-1α), promoting anabolic processes in skeletal muscle, mainly related to hypertrophy, energy pro- duction, and mitochondrial biogenesis.21,37,67,68 IL-15 also increases fatty acid oxidation, thermogenesis, and myogen- esis, and promotes glucose uptake by activating the JAK3/STAT3 signaling pathway, which upregulates the gene expression of GLUT4 and its translocation to the sar- colemma.69,70 Individuals with metabolic diseases, such as obesity and type 2 diabetes mellitus, conditions associated with MASLD, exhibit lower expression and secretion of muscu- lar IL-15. This reduction is related to an increased risk of developing sarcopenia.66 Increased circulating levels of IL- 15 have been observed to improve insulin resistance in women, a typical metabolic feature in MASLD.71,72 In ad- dition, increased expression and secretion of IL-15 from skeletal muscle into the circulation can lead to decreased body fat and inhibition of adiposity in obese mice.73 This reduction in fat mass results from a decline in free fatty acid deposits in adipose tissue, inducing the input of energetic substrates to skeletal muscle.69,74 As mentioned above, IL-15 is a myokine mainly secreted by skeletal muscle in response to exercise, promoting mus- cle hypertrophy, energy production, and overall metabolic health. However, whether IL-15 can improve muscle func- tion by enhancing energetic, metabolic, or anabolic pro- cesses in MASLD remains unknown. Further research is needed to determine whether IL-15 can be a potential ther- apeutic agent for improving muscle function and metabolic outcomes in patients with MASLD (Figure 1). - 280 - Impact of myokines on chronic liver diseases Eur J Transl Myol 35 (3) 13365, 2025 doi: 10.4081/ejtm.2025.13365 Irisin Irisin is a 12 kDa myokine primarily synthesized and se- creted by skeletal muscle, with smaller quantities produced in the liver and adipose tissue.75,76 While irisin is known to target white adipocytes, myocytes, and hepatocytes,77 its specific receptor has yet to be identified. Irisin expression is regulated by several factors, among them exercise, which increases its expression and secretion by a mechanism that depends on PGC-1α.75,78 This mechanism involves the pro- duction of fibronectin type III domain-containing protein 5 (FNDC), a membrane protein that undergoes proteolytic cleavage to form irisin.79 The overall steps to increase irisin expression by exercise are i) upregulation of PPAR-γ, a co- activator of PGC-1α in skeletal muscle, ii) subsequent el- evation of FNDC5 expression driven by increased PGC-1α levels, iii) the generation of irisin via proteolytic cleavage of FNDC5 at the cell membrane through a proteolytic enzyme yet unknown.17,80 The expression and secretion of Irisin from skeletal mus- cles have been debated in recent years due to inconsis- tencies in results regarding the levels of this myokine in response to exercise. These discrepancies are often attrib- uted to variations in detection methods (e.g., ELISA, com- mercial kits), highlighting the need for more rigorous evaluation to clarify and understand the regulation of irisin through exercise.81-84 Functionally, Irisin induces myogenesis and mitochondrial biogenesis in skeletal muscle, offering protection against sarcopenia.80,85 Irisin elevates protein anabolism by in- creasing IGF-1 production and activating protein synthe- sis-associated signaling pathways (phosphoinositide 3-kinase (PI3K)/protein kinase B (33), mTOR). This ef- fect favors muscle hypertrophy and activation of progen- itor stem cells in skeletal muscle (satellite cells). In addition, irisin reduces the activity of protein catabolic pathways (e.g., a reduction in the levels of atrogin-1 and MuRF-1)80,84 and may inhibit the expression of catabolic myokines, such as myostatin. Thus, the antecedents sup- port the idea that an experimental approach using exogen- ous irisin could be a helpful strategy in the management of sarcopenia.86 Interestingly, a transition of high levels of irisin to a significantly lower level will predict the devel- opment of sarcopenia in MASLD.87 Irisin also affects tissues beyond skeletal muscle, particu- larly adipose tissue, enhancing thermogenesis and energy expenditure.88 Moreover, Irisin causes changes in adipose tissue, reducing white adipose tissue and increasing Brown Adipose Tissue (BAT), such as gene expression, morphol- ogy, and mitochondrial activity. This mechanism and ther- mogenesis depend on PGC-1α dependent increased expression of UCP1.89 Irisin also affects the liver, regulating glucose and lipid metabolism by reducing gluconeogenesis and promoting glycogenesis, thus improving glucose homeostasis via ac- tivation of PI3K/Akt33 and AMPK pathways.90,91 Regard- ing lipid metabolism, irisin prevents lipid accumulation by enhancing lipolysis in hepatocytes and lowering cho- lesterol and triglyceride levels through AMPK activation and subsequent inhibition of sterol regulatory element- binding transcription factor 2 (SREBP2), a key regulator of cholesterol homeostasis.92 Despite evidence suggesting that serum irisin levels are elevated in patients with MASLD, correlating with its severity,93,94 caution must be considered due to the small sample size, leading to results that must be clarified.84 Despite these uncertainties, Irisin holds potential as a ther- apeutic target in treating complications associated with obesity, including MASLD, although the mechanisms un- derlying these benefits remain to be fully elucidated. Fu- ture research should focus on clarifying the role of irisin in alterations observed in MASLD, such as hepatic oxi- dative stress and apoptosis, and its role in hepatocellular carcinoma.17 In summary, irisin is a myokine with beneficial effects on adipose tissue, liver, and skeletal muscle. In MASLD, el- evated irisin levels are associated with abnormal body com- position, insulin resistance, glucose metabolism, plasma lipid levels, and liver enzyme activity (Figure 1). Other myokines related to MASLD Several new myokines have been studied for their potential roles in MASLD in recent years. Leukemia inhibitory factor (LIF) Leukemia inhibitory factor (LIF) is a 20 kDa myokine se- creted by neurons, cardiac and skeletal muscle. Its expres- sion increases in skeletal muscle, but not in serum, after resistance exercise, stimulating satellite cell prolifera- tion.95,96 Additionally, LIF production and secretion have been observed in human myotube cell cultures following electrical stimulation, suggesting that LIF is a myokine with an autocrine effect on skeletal muscle.97 In MASLD, serum LIF levels are associated with the sev- erity of hepatic in patients with liver damage and a murine model of obesity.98 Patients with liver fibrosis, lobar in- flammation, and increased serum levels of Alanine Trans- aminase (ALT) and aspartate Aminotransferase (AST) (two hepatic enzymes related to liver damage) showed an increase in levels of LIF.91 Interestingly, overexpression of LIF in adipose tissue produces a protective function in an MASLD condition, reducing the inflammatory state by reducing the expression of pro-inflammatory cytokines such as tnf-α, il6, and ccl2. In addition, under these con- ditions, an improvement in fatty tissue metabolism, glu- cose tolerance, and insulin sensitivity has been observed. The same beneficial effects were observed in the liver when the LIF receptor (LIFR) was overexpressed in a mu- rine model of obesity, indicating that the LIF receptor has a protective role in the liver.98,99 However, further studies are needed to clarify the function of LIF in skeletal muscle in MASLD (Figure 1). Fibroblast growth factors 21 (FGF21) FGF21 is a molecule expressed by various tissues, includ- ing the liver, adipose tissue, and skeletal muscle, in re- sponse to different stress states, such as cold exposure, fasting, and exercise. FGF21 acts through the FGF recep- tor (FGFR) and the cofactor β-klotho.96 During resistance exercise, FGF21 expression increases in skeletal muscle, - 281 - Impact of myokines on chronic liver diseases Eur J Transl Myol 35 (3) 13365, 2025 doi: 10.4081/ejtm.2025.13365 contributing to converting slow-twitch fibers muscle to fast-twitch fibers in the gastrocnemius muscle of mice. In addition, FGF21 decreases TGF-β1 signaling and in- creases MAPK p38 signaling in muscle cells, increasing glucose uptake and reducing lipid accumulation in the muscle.100,101 However, it has also been reported that FGF21 is increased in skeletal muscle in steatosis con- ditions.102 In FGF21 KO mice was observed a protective effect on muscle mass loss during starvation, supporting the idea that FGF21 could be an anti-sarcopenic soluble factor by preventing decreased protein synthesis and al- tered mitophagy.103,104 Regarding MASLD, FGF21 reduces triglyceride accumu- lation in hepatocytes (steatosis) due to lipolysis inhibition, decreasing the concentration of fatty acids in the circula- tion and reducing their accumulation in the liver.105 FGF21 also decreases plasma glucose in ob/ob mouse models and mitigates hepatic oxidative stress by activating the FGFR/AMPK/Sirt1 signaling pathway, which upregulates antioxidant enzymes such as Nrf2 and SOD.106,107 More- over, FGF21 has been shown to reduce hepatic inflamma- tion in MASLD by activating the Nrf2 pathway and inhibiting NF-κB signaling.108 In summary, FGF21 is a myokine regulated in skeletal muscle by exercise, with its role in muscle mass regulation depending on the stimulus and the physiological context. It can participate in muscle mass gain through inhibiting TGF-β1 and is associated with the development of sar- copenia due to starvation. Concerning MASLD, circulat- ing levels of FGF21 are elevated and directly correlate with the severity of liver damage and steatosis (Figure 1). Myonectin Myonectin is a myokine secreted in response to exercise and belongs to the C1q/TNF (CTRP) protein family.109 This myokine participates in the absorption of fatty acids through the increase in the expression of Fatty Acid Trans- porters (FATP1) and fatty acid binding proteins (Fabp1 and Fabp4).73 Myonectin also reduces starvation-induced autophagy by decreasing the formation of LC3-dependent autophagosomes and p62.110 Additionally, myonectin has been described as a potentiator of protein synthesis through the PI3K/Akt/mTOR signaling pathway, indicat- ing that this myokine can positively regulate muscle mass by increasing protein synthesis and decreasing the degra- dation process, specifically autophagy. Some studies have associated myonectin with a protective role in skeletal muscle through AMPK/PGC1a signaling, attenuating sar- copenia induced by denervation and dexamethasone.20,73,111 In MASLD, various metabolic disorders, such as diabetes mellitus, have been associated with levels of myonectin. For instance, in patients with type 2 diabetes mellitus and obesity, the concentration of myonectin in the serum has been negatively associated with an increase in circulating triglycerides, LDL, and total cholesterol,112,113 which may reflect a state of resistance to myonectin. Interestingly, moderate and high-intensity exercise can increase the serum levels of myonectin in MASLD patients, indicating a possible improvement in lipid metabolism by exercise- induced elevations in circulating myonectin.114-116 To summarize, myonectin is a myokine whose expression is regulated by exercise and is protective against muscle mass loss in sarcopenia conditions. However, more re- search is still needed to understand its association with MASLD and its molecular roles in skeletal muscle and the liver (Figure 1). Conclusions and perspectives Skeletal muscle releases myokines under physiological and pathological conditions. Some myokines are released at rest, while others are secreted during or after muscle contraction (e.g., exercise). These myokines can function in an autocrine, paracrine, or endocrine manner in various tissues and organs, such as the liver and adipose tissue. Some well-known myokines include irisin, myostatin, IL- 6, IL-15, IGF-1, LIF, FGF21, and myonectin. Some myokines are produced and secreted during exer- cise in response to muscle contraction. They perform es- sential functions such as increasing muscle mass, protecting against muscle degradation, and promoting en- ergy metabolism and glucose homeostasis. Myokines have shown detrimental effects in pathological conditions, including MASLD. For instance, irisin can af- fect body composition, while myostatin, IL-6, and irisin can affect insulin and glucose homeostasis. IL-6 is asso- ciated with liver injury and chronic inflammation, while myostatin, IGF-1, and IL-6 affect skeletal muscle mass. Some myokines, such as LIF and FGF21, are related to the severity of MASLD (i.e., increased steatosis or in- creased circulating triglycerides). The precise roles of myokines in MASLD must still be fully understood. Future research must include well-con- trolled clinical studies to determine their functions and biochemical mechanisms of action in humans. Myokines have the potential to be new targets for preventing or treat- ing sarcopenia in metabolic diseases like MASLD. List of abbreviations FGF21, Fibroblast growth factors 21 GDF8, Growth differentiation factor 8 IGF-1, Insulin-like growth factor 1 IL-6, Interleukin-6 IL-15, Interleukin-15 IR, Insulin resistance LIF, Leukemia inhibitory factor MASLD,: Metabolic dysfunction-associated steatotic liver disease MAFbx1/atrogin-1, Muscle-specific F-box protein 1 MuRF-1, Muscle RING-finger protein1 PI3K, Phosphoinositide 3-kinase /protein kinase B TGF-β, Transforming growth factor-beta TNF-α, Tumor necrosis factor-alpha UPS, Ubiquitin-proteasome system Funding The manuscript was supported by research grants from the National Fund for Science and Technological Devel- - 282 - Impact of myokines on chronic liver diseases Eur J Transl Myol 35 (3) 13365, 2025 doi: 10.4081/ejtm.2025.13365 opment (FONDECYT 1241947 [C.C-V.], 1211879 [D.C.], 1211962 [L.P.]); Agencia Nacional de Investigación y De- sarrollo (ANID)-Millennium Science Initiative Program - ICN09_016 / ICN 2021_045: Millennium Institute on Im- munology and Immunotherapy (ICN09_016 / ICN 2021_045; former P09/016-F) [C.C-V.]). Proyecto Núcleo UNAB (DI-03-23/NUC [C.C-V.]; DI-02-22/NUC [C.O.]). Beca Doctorado Nacional ANID (21212005 [M.V-B.], 21201447 [F.A.]). Beca VRI UNAB N° DI-05-21/INI [M.V-B.]. Conflict of interest The authors declare that they have no conflict of interest. Ethical approval All animal procedures complied with international, na- tional, and institutional animal care guidelines and were approved by the Animal Ethics Committee at the Univer- sidad Andrés Bello Committee. Author contributions Conceptualization, FA, and CC-V; Methodology, FA, MV- B, and CC-V; Validation, FA, MV-B, DC, LP, CO, and CC- V; Investigation, FA, M V-B, DC and CC-V; Visualization, FA, MV-B, CO, and CC-V; Supervision CC-V; Project ad- ministration, CC-V; Writing – Original Draft Preparation, FA, MV-B, DC LP, CO, CF, and CC-V; Writing – Review & Editing, FA, MV-B, DC, CF, LP, CO, and CC-V Corresponding author Claudio Cabello-Verrugio, Center for Research on Pan- demic Resilience, Faculty of Life Sciences and Institute of Public Health, Universidad Andres Bello. Santiago, 8370146, Chile. Tel./Fax: +56.2.27703665. ORCID ID: 0000-0001-7273-2102 E-mail: claudio.cabello@unab.cl Co-authors Francisco Aguirre ORCID ID: 0000-0001-8103-9473 E-mail: f.aguirregalaz@uandresbello.edu Mayalen Valero-Breton ORCID ID: 0000-0001-6552-2262 E-mail: m.valerobreton@uandresbello.edu Daniel Cabrera ORCID ID: 0000-0001-9634-725X E-mail: dacabrera@uandes.cl Luis Peñailillo ORCID ID: 0000-0001-7697-9700 E-mail: luis.penailillo@unab.cl Carolina Otero ORCID ID: 0000-0002-8608-9813 E-mail: maría.otero@unab.cl Claudia Fredes ORCID ID: 0000-0002-5526-1801 E-mail: claudia.fredes@unab.cl References 1. Teng ML, Ng CH, Huang DQ, et al. Global incidence and prevalence of nonalcoholic fatty liver disease. Clin Mol Hepatol 2023;29:S32-s42. 2. Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)(1). Autophagy 2021;17:1-382. 3. Zarghamravanbakhsh P, Frenkel M, Poretsky L. 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Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Submitted: 10 November 2024. Accepted: 1 July 2025. Early access: 23 July 2025. - 287 -