Follistatin

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used to treat obesity and metabolic diseases, yet their early impact on body composition and circulating regulators of muscle and bone remain unclear. This study aimed to assess early effects of liraglutide on total and regional body composition and associated changes in circulating markers of muscle and bone metabolism.

Abstract

In this issue of Neuron, Li et al.1 show that follistatin-like 1 (FSTL1) emerges as a critical hypothalamic insulin sensitizer, whose pharmacological targeting attenuates body weight gain and improves systemic glucose metabolism, highlighting brain insulin signaling amplification as a promising strategy against obesity and associated metabolic disorders.

Abstract

Sarcopenia is a prevalent and debilitating skeletal muscle disorder in the aging population, characterized by progressive loss of muscle mass, strength, and function. Despite its significant impact on mobility, independence, and healthcare systems worldwide, effective pharmacological treatments remain limited. Recent advances in the understanding of sarcopenia pathophysiology have identified myostatin-a potent negative regulator of muscle growth-as a promising therapeutic target. Myostatin inhibitors-comprising direct agents such as monoclonal antibodies and small molecules, as well as indirect modulators including follistatin-based strategies and other pathway regulators-have demonstrated encouraging results in preclinical and early clinical studies by increasing muscle mass and improving muscle function. This comprehensive review summarizes current knowledge of myostatin's molecular mechanisms in muscle homeostasis, evaluates the efficacy and safety of various myostatin-targeted therapies in sarcopenia, and discusses the translational challenges and future directions for clinical application. The integration of myostatin inhibition into therapeutic regimens offers the potential to address a critical unmet need in sarcopenia management and improve the quality of life for elderly individuals.

Abstract

The cardioprotective mechanisms through which the heart directly senses exercise remain incompletely defined. In this study, wild-type C57BL/6J and cardiomyocyte-specific Piezo1 knockdown mice were subjected to myocardial infarction (MI) and moderate treadmill exercise. We found that treadmill exercise significantly increased myocardial Piezo1 and SERCA2 expression and improved ejection fraction and short-axis shortening fraction in MI mice through echocardiography, histological staining, and molecular biology analysis. In contrast, Piezo1 knockdown impaired exercise-induced reductions in cardiomyocyte apoptosis, survival benefits, and attenuation of fibrosis. In HL-1 cells, mechanical stretch upregulated Piezo1 and suppressed H2O2-induced apoptosis via the p38MAPK-YAP1 pathway, while Piezo1 deficiency abolished this protective signaling. In addition, Piezo1 mediates the expression of FSTL1 and GDF5, which are key molecules of exercise-induced cardioprotection. These findings identify Piezo1 as a mechanosensor essential for exercise-triggered myocardial protection and highlight its potential therapeutic relevance for MI patients' recovery.

Abstract

Glomerular extracellular matrix protein accumulation, mediated largely by mesangial cells(MC), is a defining feature of diabetic kidney disease(DKD). Previously we showed that TGFβ1, a profibrotic cytokine in kidney fibrosis, inhibits expression of the antifibrotic follistatin through induction of microRNA-299a-5p. Whether this microRNA contributes to DKD is unknown. We show that microRNA-299a-5p is increased in mouse and human diabetic kidneys, and by high glucose in primary MC. Overexpression of microRNA-299a-5p in MC increased basal ECM protein production. Conversely, microRNA-299a-5p inhibition prevented the glucose-induced profibrotic response. Bioinformatics screening revealed that cripto-1 is also a target of microRNA-299a-5p. Induction of microRNA-299a-5p by high glucose mediated the MC fibrotic response by inhibiting follistatin and cripto-1 which led to increased activin A and TGFβ1 signaling. In vivo, microRNA-299a-5p inhibition reduced clinical markers of DKD, and was associated with increased expression of follistatin and cripto-1. Thus, microRNA-299a-5p is an important mediator of glucose-induced profibrotic responses in diabetic kidneys.

Abstract

Myostatin and follistatin are the regulators of muscle growth and pivotal proteins that regulate muscle tissue function. An integrated approach is HIIT and resistance training provides a holistic strategy for promoting healthy aging and maintaining functional abilities, potentially through the modulation of myostatin and follistatin levels. This study aims to assess the effect of high-intensity interval training and resistance training on myostatin and follistatin protein concentrations in aged rats' serum and muscle tissue. In this study, 20-month-old female Sprague-Dawley rats were used in three groups: (1) Control (Con), (2) Resistance training (RT), and (3) High-intensity interval training (HIIT). The HIIT and resistance training protocols were carried out for 8 weeks and three sessions per week. The results showed serum levels and muscle tissue content of myostatin increased in the RT compared to the control group (p = 0.0001 and p = 0.04). The muscle tissue content of follistatin increased in the HIIT compared to the control group (p = 0.03). There is a significant difference in serum levels and muscle tissue content of follistatin between HIIT and RT groups (p = 0.0001 and p = 0.001). According to the roles of myostatin and follistatin in regulating muscle hypertrophy, present research shows HIIT has more effects on follistatin levels and resistance training has more effects on myostatin levels. This can indicate that according to the number of training sessions, HIIT can be a better and newer treatment method for older people.

Abstract

Myostatin (M), activin-A (A) and follistatin (F), three TGF-β superfamily members, play a role in cancer sarcopenia. The aim of our study was to assess the association of MAF in head and neck cancer (HNC) skeletal muscle loss.

Abstract

Sepsis-associated acute kidney injury (AKI) is a major cause of morbidity and mortality, and lipopolysaccharide (LPS)-induced ferroptosis is a critical mechanism of renal tubular cell injury. Follistatin-like 1 (FSTL1) is a matricellular protein implicated in inflammation and oxidative stress; however, its role in LPS-induced ferroptosis in renal tubular cells remains unknown. Human renal proximal tubular epithelial (HK-2) cells were exposed to increasing concentrations of LPS to evaluate FSTL1 expression levels. FSTL1 silencing was achieved by siRNA transfection, and its effects on PI3K/Akt signaling, apoptosis, oxidative stress, and ferroptosis were assessed using western blotting, RT-qPCR, flow cytometry, and fluorescent probes. The PI3K/Akt inhibitor LY294002 was used to validate the involvement of this pathway. FSTL1 expression was significantly upregulated by LPS in a dose-dependent manner at both the mRNA and protein levels. Silencing FSTL1 markedly increased the phosphorylation of PI3K and Akt and significantly attenuated LPS-induced apoptosis, as evidenced by increased cell viability and decreased number of Annexin V-positive cells. FSTL1 silencing also decreased reactive oxygen species and malondialdehyde levels, while enhancing superoxide dismutase activity and glutathione content. Moreover, FSTL1 silencing reduced mitochondrial ferrous iron accumulation and restored Nrf2, SLC7A11, GPX4, and FTH1, alongside decreased ACSL4 expression. These protective effects were reversed by LY294002, indicating a dependence on PI3K/Akt signaling. FSTL1 mediates LPS-induced apoptosis, oxidative stress, and ferroptosis in renal tubular cells via the PI3K/Akt pathway. Targeting FSTL1-PI3K/Akt signaling may represent a novel approach to mitigate ferroptotic injury in endotoxin-stimulated renal tubular cells, providing mechanistic insights relevant to LPS-induced tubular injury model.

Abstract

Glucagon-like peptide-1 receptor agonists treat type 2 diabetes mellitus (T2DM), obesity and related comorbidities. Generic liraglutide recently became available, increasing its accessibility. While effective for weight and glycaemic control, its impact (magnitude, timing and regional patterns) on body composition remains uncertain. This exploratory study investigated short-term effects of liraglutide on metabolic parameters, detailed body composition, and myostatin-activin-follistatin-IGF-1 (MAFI) axis components in individuals with T2DM.

Abstract

MASLD (metabolic-associated steatotic liver disease) and MASH (steatohepatitis) are closely associated with hepatic IR (insulin resistance) and T2D. Regardless, insulin-stimulated hepatic lipogenesis is considered essential for MASLD development, as mouse models of complete hepatic IR become diabetic without MASLD when fed high-fat diets. Challenging this notion, we found that male LDKO mice lacking hepatic insulin receptor substrates acutely developed MASLD if fed a fructose-enriched "MASH diet" (GAN) or high-fructose diet. Fructose potentiated hepatic re-esterification of abundant circulating fatty acids in LDKO mice, evidenced by excess 13C incorporation into the glycerol backbone-but not fatty acid chains-of hepatic triacylglyceride after gavage with [U13C]fructose. Suppressing adipose lipolysis in LDKO mice by inactivating hepatic Fst (Follistatin) prevented acute MASLD, whereas over-expressing Fst in wild-type mouse liver accelerated GAN-promoted MASLD/MASH. Compatibly, higher serum FST levels among Tübingen Diabetes Family Study participants clustered with increased adipose IR and greater hepatic triacylglyceride accumulation.

Abstract

Individuals who engage in high-intensity endurance exercise reportedly have a lower rate of mortality from metabolic diseases than do those who engage in moderate-intensity endurance exercise. However, the mechanisms underlying this association remain unclear. The cytokines C1q/tumour necrosis factor-related protein (CTRP) 3, CTRP9, and follistatin-like 1 (FSTL1) improve metabolic diseases. The secretion of these circulating cytokines is enhanced through acute endurance exercise; however, the effects of exercise intensity on this secretion have not been elucidated. We investigated the effect of exercise intensity on the circulating CTRP3, CTRP9, and FSTL1 concentrations.

Abstract

There has been a growing rate of obesity among children and adolescents in recent years. Understanding the molecular mechanisms is crucial for grasping the onset and progression. Adipose tissue is recognized for its role in endocrine functions, releasing adipokines that play a vital role in the metabolic disruptions linked to obesity. Given the involvement of adipokines such as FSTL-1 (follistatin related protein 1), FAM19A5 (family with sequence similarity to 19 member A5), and CTRP-6 (C1q/tumor necrosis factor related protein 6) in this condition, the primary goal of our study was to explore the connection between these adipokines, metabolic parameters, anthropometric data, and obesity.

Abstract

The role of myokines as a link between cardiac rehabilitation (CR) and cardiovascular benefits in patients recovering from acute coronary syndrome (ACS) is important but not well understood. We investigated the effect of CR on circulating levels of myostatin, follistatin, apelin, and follistatin-related protein 1 (FSTL1) in post-ACS patients. A total of 110 patients underwent a 2-week CR programme (group S) and were compared with 110 non-CR patients (group K). In group S, blood pressure, heart rate, anthropometrics, body composition, and serum myokine levels were measured at baseline and post-CR; in group K, these were assessed once. After CR, apelin, myostatin, and FSTL1 increased in group S. Apelin and myostatin were higher in group S post-CR compared with group K, while follistatin remained higher in group K at both time points. FSTL1 was initially higher in group K but increased post-CR in STEMI patients only; myostatin increased in NSTEMI patients. Apelin increased in STEMI patients. Apelin and myostatin levels were independent of cardiovascular risk factors. Post-CR, follistatin correlated inversely with diastolic pressure; FSTL1 was related to fat tissue, muscle mass and body mass index. CR modulates key myokines and differential myokine responses in STEMI vs. NSTEMI patients support the need for personalised rehabilitation strategies. ClinicalTrials.gov registration number: NCT03935438.

Abstract

Cardiovascular disorders are closely linked to metabolic syndrome and remain a leading cause of mortality worldwide, despite advances in early detection and treatment. Adipokines, cardiokines, and myokines play critical roles in maintaining systemic metabolic homeostasis. In this study, we measured serum levels of fatty acid binding protein 4 (FABP4), follistatin-like 1 (FSTL1), irisin, and adiponectin in 243 male patients undergoing elective coronary angiography. We investigated the associations of these biomarkers with coronary artery disease (CAD) and their correlation with metabolic syndrome status. FSTL1 levels were predicted using a Particle Swarm Optimization-enhanced Adaptive Neuro-Fuzzy Inference System (PSO-ANFIS) based on artificial intelligence. Patients with CAD exhibited significantly lower FABP4 levels (p<0.0001), and low FABP4 levels emerged as an independent predictor of CAD in logistic regression analysis (odds ratio 0.903, 95% CI 0.825-0.987, p=0.025). The combination of adiponectin, FSTL1, and irisin as a biomarker strategy demonstrated high sensitivity and specificity for diagnosing metabolic syndrome (AUC = 0.92, 95% CI 0.88-0.96). Both FSTL1 and adiponectin independently correlated with metabolic syndrome (p<0.001, odds ratio 1.039, 95% CI 1.025-1.054; p<0.001, odds ratio 0.979, 95% CI 0.971-0.988, respectively). The prediction of FSTL1 levels using PSO-ANFIS supports the concept of harmonization among metabolic messengers. These findings underscore the potential of FABP4 and FSTL1 as valuable biomarkers for diagnosing metabolic and cardiovascular diseases, thereby facilitating personalized interventions targeting organokine pathways.

Abstract

Purpose: This study sets out to analyze the correlation of ET-1, a vasoactive peptide, along with various cytokines and vascular factors, with clinical parameters and OCT/OCT-A measurements in glaucoma participants. Methods: Eyes of participants with cataract (n = 30) or glaucoma (n = 87) were examined with optical coherence tomography (OCT) and OCT angiography (OCT-A). Aqueous humor (AqH) from the examined eye and plasma were sampled during cataract or glaucoma surgery and analyzed by means of ELISA and Luminex assay to determine their levels of ET-1 and 35 proteins deemed relevant for regulation of the AqH outflow pathway, ocular perfusion (OP), and glucose metabolism. Results: Glaucomatous eyes are characterized by reductions in RNFL thickness and OP, reflected by reduced vessel density. Furthermore, significantly elevated peripheral ET-1 levels were detected in participants with glaucoma. In addition, significantly elevated AqH levels of MMP-2, MMP-3, ET-1, sEMMPRIN, ZAG, sLOX-1, follistatin, cortisol, endostatin, sTIE-2, and PDGF-BB were detected in the glaucomatous eyes, with correlation to reduced VD for APN, C3a, MMP-3, resistin, sTIE-2, and ZAG. Multivariable analysis showed a correlation of AqH APN levels with the reduced VD in glaucomatous eyes. Conclusions: The peripheral ET-1 level and the intraocular levels of APN, C3a, MMP-3, resistin, sTIE-2, and ZAG are associated with impaired OP in glaucoma. Furthermore, elevated intraocular levels of MMP-3, ZAG, and APN were identified as biomarkers for impaired perfusion in glaucoma.

Abstract

Muscle growth is a critical determinant of meat yield and quality in livestock. Although follistatin (FST) is recognized as a key regulator of skeletal muscle development and fat metabolism, its specific function in geese remains largely unexplored. In this study, we identified two transcript variants of goose FST (gFST) in Zhedong White geese: gFST-X1 (1125 bp), encoding a 343-amino acid protein with a 28-amino acid signal peptide and four conserved domains, and gFST-X2, which contains a 243 bp insertion within the gFST-X1 transcript. RT-qPCR analysis revealed that gFST mRNA expression varied across tissues from female embryos (25 days), adults (70 days), and laying geese (270 days), as well as in skeletal muscle satellite cells (SMSCs) at embryonic day 16 (E16d). Overexpression of gFST in SMSCs resulted in 3596 differentially expressed genes (DEGs), including 2247 upregulated and 1349 downregulated genes (padj < 0.01). Key stemness markers (PAX7, PAX3) and myogenic regulators (MYOG, MYOD, MYF5) were significantly downregulated, whereas genes associated with lipid metabolism (PPARG, FABP5, ACSL5) and myosin-related processes (MYO1D, MYO1F, MYO1E) were markedly upregulated (padj < 0.01). Functional enrichment analysis linked these DEGs to the TGF-β, PPAR signaling, fatty acid metabolism, and Notch signaling pathways. These transcriptomic findings were further validated by qRT-PCR. Collectively, our results demonstrate the dual regulatory role of gFST in skeletal muscle development and provide new mechanistic insights into muscle development in geese.

Abstract

Follistatin-like 1 (FSTL1) is a signaling molecule that modulates energy metabolism in peripheral tissues and is also expressed in the brain. However, whether hypothalamic FSTL1 regulates carbohydrate/lipid metabolism and energy balance remains unknown. Here, we show that FSTL1 is enriched in the hypothalamus, especially the arcuate nucleus (ARC). FSTL1 expression is decreased in diet-induced obese (DIO) and db/db mice. Agouti-related peptide (AgRP) neuron-specific Fstl1 deletion increased food intake, decreased energy expenditure, and impaired insulin sensitivity in DIO mice. Conversely, Fstl1 overexpression in AgRP neurons resulted in the opposite phenotypes. Insulin signaling was required for the anti-obesity effect of hypothalamic FSTL1. Intranasal FSTL1 delivery promoted weight loss and improved insulin sensitivity in DIO mice. Mechanistically, FSTL1 interacts with Akt, an intracellular mediator of insulin signaling, to inhibit forkhead box protein O1 (FoxO1) nuclear translocation. Our findings identify hypothalamic FSTL1 as a key mediator counteracting DIO and provide a potential pharmacological strategy for obesity-related metabolic disorders.

Abstract

Sympathetic tone is a central signaling axis inhibiting osteogenesis; however, the combination of durable local and systemic sympathetic effects on bone argues that multiple mechanisms, including yet-undiscovered pathways, are involved. Here, we found that sympathetic nerves constituted a component of the skeletal stem cell (SSC) niche: mice with conditional deletion of the classical axonal repellent Slit2 in sympathetic nerves (Slit2th mice), but not in bone stem/progenitor cells or sensory nerves, showed osteopenia due to an increase in sympathetic innervation and an associated decrease in SSCs. Mice with increased skeletal sympathetic innervation displayed impaired SSC niche function in an SSC orthotopic transplantation and engraftment system. Follistatin-like 1 (FSTL1) is a SLIT2-regulated soluble factor suppressing SSC self-renewal and osteogenic capacity. Accordingly, ablation of Fstl1 in sympathetic neurons enhanced SSC-driven osteogenesis and attenuated the bone loss seen in Slit2th mice. Together, the findings indicate that SLIT2 is a regulator of a sympathetic nerve-mediated SSC niche.

Abstract

Gliomas exploit various molecular pathways to promote their survival, proliferation, and invasion. Recent studies reveal the complex neuron-glioma interaction and BDNF plays a major role in this interaction. However, it's unclear whether and how the BDNF-mediated cross-talk between neurons and gliomas is regulated. FSTL4 is reported to negatively regulate BDNF maturation. Here, we hypothesized that neuronal FSTL4 may negatively regulate BDNF-mediated neuron-glioma cross-talk. By using a combination of approaches like chemogenetic activation of primary neurons and CRISPR knockout/activation of endogenous FSTL4, we show that activated primary neurons support the proliferation of co-cultured glioma cells and neuronal BDNF secretion mediates this neuron-glioma interaction via activating TrkB in glioma cells. In addition, this process is negatively regulated by neuronal FSTL4 as its CRISPR KO in primary neurons further supports the proliferation of co-cultured glioma cells. Importantly, CRISPR activation of endogenous FSTL4 expression in primary neurons results in impaired ability to support co-cultured glioma cells, highlighting the therapeutic potential of activating endogenous FSTL4 for glioma treatment. Taken together, our study shows that the FSTL4/BDNF/TrkB axis plays an essential role in fine-tuning the neuron-glioma interaction and targeting this interplay with CRISPR tools may help to develop novel therapeutic strategies.

Abstract

Cancer-associated cachexia (CAC) is a severe metabolic disorder characterized by involuntary weight loss, skeletal muscle atrophy and adipose tissue depletion. It is a major contributor to morbidity and mortality in the advanced stages of various cancers. However, the impact of CAC on the pancreas remains largely unexplored.

Abstract

Reproductive efficiency in sheep is influenced by complex interactions between the endocrine and immune systems, particularly during early pregnancy. Immunomodulators such as levamisole are known to enhance immune responses and have been investigated for their potential to improve reproductive outcomes in various animal species. However, the effects of levamisole administered at the time of breeding on both pregnancy rates and key immunoendocrine markers in ewes remain unclear. This study aimed to evaluate the effects of levamisole, administered at varying doses during breeding, on pregnancy rates and selected immune and endocrine parameters in ewes. A total of 30 ewes were randomly assigned to three groups (n = 10 each): a control group received subcutaneous saline; the second group received levamisole at 2.5 mg/kg; and the third group received 7.5 mg/kg, all administered at the time of breeding. Blood samples were collected on days 0, 10, and 20 post-breeding. Levels of IFN-γ, IL-2, TNF-α, progesterone, activin A, activin B, follistatin, and total immunoglobulin (Ig) were measured using commercial ELISA kits.

Abstract

The COVID-19 pandemic has revealed significant secondary complications affecting musculoskeletal (MSK) health, especially in patients with pre-existing conditions. This review synthesizes data from clinical and experimental studies on key MSK biomarkers, including cartilage oligomeric matrix protein (COMP), hyaluronic acid (HA), osteocalcin, alkaline phosphatase (ALP), procollagen type I N-terminal peptide (PINP), osteopontin (OPN), matrix metalloproteinases (MMP-3 and MMP-9), myostatin, IGF-1, follistatin, and creatine kinase. COVID-19 is associated with decreased COMP and osteocalcin levels, indicating cartilage degradation and impaired bone formation, alongside elevated HA, ALP, PINP, OPN, and MMPs, reflecting increased joint inflammation, bone remodeling, and tissue breakdown. Changes in myostatin, IGF-1, follistatin, and creatine kinase levels have been shown to be linked with COVID-19-related sarcopenia. These biomarker alterations provide insight into the underlying mechanisms of MSK damage in COVID-19 patients and highlight the potential for using these markers in early diagnosis and management of post-COVID musculoskeletal disorders. Further longitudinal research is essential to develop targeted therapies aimed at mitigating long-term MSK complications in affected individuals.

Abstract

Cardiovascular diseases, which are among the most common diseases of the population and among the leading causes of death, are a constant topic of many research centers. A deeper understanding of their pathogenesis may contribute to the development of innovative diagnostic and therapeutic techniques. Recently, the role of myokines-a group of cytokines secreted mainly by muscle cells-has been increasingly emphasized in the development of these diseases. Both their excess and deficiency can cause undesirable effects that are involved in the pathomechanism of these diseases. In this review, we focus on the latest studies on the role of myonectin, irisin, musclin, follistatin-like1 (FSTL1), dermcidin, apelin, and myostatin in the pathogenesis of coronary artery disease, heart attack, heart failure, and hypertension. In particular, we look at myostatin and irisin in the context of the development of heart failure and decreased levels of apelin with higher cardiovascular risk in a group of patients with rheumatoid arthritis.

Abstract

Chronic airway diseases, including chronic obstructive pulmonary disease (COPD), asthma, and asthma COPD overlap (ACO), are characterized by complex inflammatory processes in which Activin A-a key member of the TGF-β superfamily-is implicated. Although its role in the stable state of these diseases has been extensively studied, data regarding its involvement during exacerbations remain limited. Our objective was to investigate the dynamics of Activin A in sputum and serum during acute exacerbations and subsequent convalescence in patients with chronic airway diseases.

Abstract

This study provides the first evidence related to the identification of microbial strains closely associated with muscle strength enhancement, independent of the host's genetic background. Fecal transplants from humans into mice revealed a significant impact of gut bacteria on muscle strength, with some mice experiencing increases, while others showed no change or decreases. Interestingly, analysis of the fecal and gastrointestinal tract bacteria from each mouse classified by the degree of muscle strength revealed significant differences based on muscle strength. Furthermore, a more diverse microbial community was observed in the gastrointestinal tract compared to the feces. Further investigation identified two bacterial species, Lactobacillus johnsonii (L. johnsonii) and Limosilactobacillus reuteri (L. reuteri), that are related to improved muscle strength. Indeed, we confirmed that the supplementation with these bacteria in aged mice significantly enhanced their muscle strength by increasing the mRNA expression levels of follistatin (FST) and insulin-like growth factor-1 (IGF1) in muscle tissue. Overall, this study provides the first evidence that specific gut bacteria can directly improve muscle strength and introduces a novel approach to studying the gut microbiome's influence on complex traits.

Abstract

Activin, GnRH, and estrogen are key endocrine inputs known to regulate the GnRH receptor (GnRHR) promoter; however, it has become increasingly evident that the mechanisms regulating the GnRHR promoter vary by model and species. To explore these differences, transgenic mice harboring either a wild-type mouse GnRHR (mGnRHR) or sheep (oGnRHR) GnRHR promoter fused to luciferase (-LUC) were infected with an adenovirus overexpressing follistatin, neutralizing activin and decreasing serum concentrations of FSH in both animal models. However, follistatin overexpression in the oGnRHR-LUC mouse more than doubled luciferase expression, whereas in the mGnRHR-LUC animals it led to a 40% decrease in luciferase expression. Thus, the divergent transcriptional responses of the mouse and sheep GnRHR genes to activin appear to be reliably recapitulated in transgenic mice. To further elucidate mechanisms regulating oGnRHR expression, a mouse with a mutated cyclic AMP response element (µCRE) in the proximal oGnRHR-LUC promoter was developed. Using an electrophoretic mobility shift assay, a specific and high affinity interaction of the ovine CRE with nuclear components exists, but these are not modified in the presence of E2, indicating that CRE binding protein (CREB) is necessary but not sufficient to mediate E2 input to oGnRHR expression.

Abstract

Myokines, important signalling molecules in regulation of homeostasis in a post-injury state, have not been studied in burn patients. Here, we aimed to analyse dynamic changes in systemic and local concentrations of myokines and evaluated their associations with the mode of physiotherapy in burn patients. In this pilot study, 20 burn patients underwent repeated functional proprioceptive stimulation and conventional physiotherapy. Plasma, skeletal muscle, and fatty tissue biopsies were obtained before and after physiotherapy and selected myokines were analysed by multiplex assays. There was no significant difference in myokine expression in relation to the mode of physiotherapy (p > 0.05); both modes were associated with a pattern of decreasing brain-derived neurotrophic factor (BDNF) plasma concentrations immediately after exercise. While BDNF plasma concentrations and follistatin-like 1 (FSTL1) muscle concentrations significantly increased over the 40-day post-injury hospitalization, plasma concentrations of FSTL1, fatty acid-binding protein 3 (FABP3), and interleukin 6 (IL6) decreased. In addition, FSTL1 in skeletal muscle increased during hospitalization in burn patients regardless of the physiotherapy mode. Significant positive correlations among FABP3, FSTL1, and IL6 in plasma were observed (r > 0.55); moreover, BDNF plasma concentrations significantly negatively correlated with those of FABP3 and FSTL1 (r = -0.53 and -0.45, respectively). In conclusion, we have identified a range of myokines potentially associated with rehabilitation and recovery in burn injury patients, which could help in further study of muscle wasting prevention in critically ill patients. We demonstrated the suitability of the panel for studying dynamic changes in concentrations of multiple myokines. BDNF, FABP3, and FSTL1 were shown to be the most promising myokines for further research in this area.

Abstract

Sarcopenia is an age-associated progressive deterioration of skeletal muscle, not only affecting the muscle function of elderly individuals but also contributing to various health issues and increased mortality. Current diagnostic tools are faced with limitations, hindering their widespread clinical application. This review examines the potential of myokines, peptides released from contracting muscles, as innovative biomarkers for sarcopenia. We explore the wide range of auto-, para-, and endocrine functions of myokines and the pathways of their physiological action, as well as address ongoing research results on the role of myokines as biomarkers for the timely diagnosis of sarcopenic individuals. Of all myokines, the ones that show the highest potential include irisin, myostatin, follistatin and brain-derived neurotrophic factor (BDNF). Their physiological action is exerted through complex pathways involving multiple molecules. Most studies show that these molecules can be used as biomarkers for the timely diagnosis of sarcopenia, whether by using each one individually or as a panel of biomarkers. However, several studies showed no correlation between the plasma levels of these peptides and a sarcopenia diagnosis. Finally, a number of studies also exhibited gender-affected relationships. While the quality of studies is promising, research on the use of myokines as biomarkers of sarcopenia is needed to more accurately determine the cut-off plasma values of such markers. By overcoming the shortcomings of existing methodologies, utilizing myokines in daily clinical practice could offer a promising path toward more effective prevention, diagnosis, and treatment strategies, ultimately improving outcomes for the aging population.

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition intricately linked to systemic metabolic impairments. Among the molecular mediators implicated in its pathogenesis, follistatin and plasminogen activator inhibitor-1 (PAI-1) play a significant role in inflammatory, fibrotic, and metabolic processes. However, the interplay between these two biomarkers in the context of MASLD remains poorly understood. Objective: This study analyzes the relationship between follistatin and PAI-1 in subjects with MASLD and obesity. It also assesses changes in these biomarkers and metabolic parameters after a dietary intervention that involves increasing one serving of vegetables and reducing one serving of carbohydrates. Methods: Forty-four individuals with MASLD and obesity participated in a two-month dietary intervention. The concentrations of PAI-1 and follistatin were measured at baseline and post-intervention. Multivariate linear regression models, adjusted for age, gender, waist circumference, and insulin resistance (measured by HOMA-IR), were employed to analyze the association between the two biomarkers. Results: Following the dietary intervention, PAI-1 levels showed a significant reduction (from 35.76 to 33.54 ng/mL; p < 0.001), whereas follistatin concentrations remained relatively stable (from 43.6 to 45.3 ng/mL; p = 0.392). Post-intervention, multivariate analysis reveals that higher follistatin levels were independently associated with lower PAI-1 levels. The inclusion of follistatin in the regression model enhanced the estimated dietary effect on PAI-1 reduction (from -0.145 to -0.194), suggesting a possible independent modulatory role of follistatin in the regulation of PAI-1 levels. Conclusions: These findings indicate that follistatin may act as an inhibitory regulator of PAI-1 expression in individuals with MASLD and obesity, potentially contributing to reductions in the prothrombotic status during dietary intervention. The data suggest a synergistic relationship between follistatin and PAI-1 in the regulation of prothrombotic status in conditions of hepatic steatosis.

Abstract

Type 2 diabetes (T2D) is a chronic metabolic disorder associated with aging, systemic inflammation, and increased long-term mortality. Identifying prognostic biomarkers may improve risk stratification and guide personalized interventions. This study aimed to evaluate the long-term prognostic value of circulating biomarkers related to inflammation, metabolic stress, and organ damage in individuals with T2D.