GDF11 (Protein of Juvenility) and GDF15 (Protein of Senility) in the Plasma of Patients with Sleep Apnea Syndrome: a Pilot Study.

We performed a matched-pair analysis of the content of GDF11 and GDF15 proteins in the plasma of patients (56 middle-aged men) with obstructive sleep apnea syndrome (OSAS) and healthy volunteers (27 men with no complaints of sleep disorders). The groups were comparable in terms of age and presence of chronic diseases. No statistically significant differences in GDF11 content in the studied groups were revealed, while the content of GDF15 in the OSAS group was 1.3 times higher. These results require further research from the viewpoint of geriatric somnology and molecular biology.

GDF11 protects against mitochondrial-dysfunction-dependent NLRP3 inflammasome activation to attenuate osteoarthritis.

INTRODUCTION: Osteoarthritis (OA) is a highly prevalent degenerative disease worldwide, and tumor necrosis factor (TNF-α) is closely associated with its development. Growth differentiation factor 11 (GDF11) has demonstrated anti-injury and anti-aging abilities in certain tissues; however, its regulatory role in OA remains unclear and requires further investigation. OBJECTIVES: To identify whether GDF11 can attenuate osteoarthritis. To exploring the the potential mechanism of GDF11 in alleviating osteoarthritis. METHODS: In this study, we cultured and stimulated mouse primary chondrocytes with or without TNF-α, analyzing the resulting damage phenotype through microarray analysis. Additionally, we employed GDF11 conditional knockout mice OA model to examine the relationship between GDF11 and OA. To investigate the target of GDF11's function, we utilized NLRP3 knockout mice and its inhibitor to verify the potential involvement of the NLRP3 inflammasome. RESULTS: Our in vitro experiments demonstrated that endogenous overexpression of GDF11 significantly inhibited TNF-α-induced cartilage matrix degradation and inflammatory expression in chondrocytes. Furthermore, loss of GDF11 led to NLRP3 inflammasome activation, inflammation, and metabolic dysfunction. In an in vivo surgically induced mouse model, intraarticular administration of recombinant human GDF11 alleviated OA pathogenesis, whereas GDF11 conditional knockout reversed this effect. Additionally, findings from the NLRP3-knockout DMM mouse model revealed that GDF11 exerted its protective effect by inhibiting NLRP3. CONCLUSION: These findings demonstrate the ability of GDF11 to suppress TNF-α-induced inflammation and cartilage degeneration by preventing mitochondrial dysfunction and inhibiting NLRP3 inflammasome activation, suggesting its potential as a promising therapeutic drug for osteoarthritis.

Liraglutide reduces bone marrow adipogenesis by miR-150-5p/ GDF11 axis in diabetic rats.

In recent years, a common-used antidiabetic drug, liraglutide, was identified with extra effects on lipid metabolism. Its effects against excessive lipid deposition in bone marrow were gained much attention but not well established. Our aim in the present study is to explore the interaction of miRNAs-mRNAs altered by liraglutide administration during bone marrow adipogenesis in diabetes. To establish the diabetic animal model, rats were treated with high fat diet (HFD) and STZ injection. We then identified the lowering effect of liraglutide on lipids metabolism in the diabetes. During this process, high-throughput sequencing and bioinformatics analyses on miRNAs extracted from bone marrow mesenchymal stem cells (BMSCs) were conducted after liraglutide administration. We then identified five differentially expressed miRNAs (miRNA-150-5p, miRNA-129-5p, miRNA-201-3p, miRNA-201-5p, and miRNA-214-5p). The expressions of the DE miRNAs were verified as temporal specific expression patterns in Day 3 and in Day 7. Among them, miRNA-150-5p expression was more stable and consistent with the sequencing data. Of interest, miR-150-5p overexpression facilitated adipogenesis of BMSCs. But this promotion was alleviated by liraglutide. The predicted target gene of miR-150-5p, GDF11, was validated to be involved in liraglutide alleviated BMSCs' lipid accumulation in diabetes. In vitro, liraglutide increased the GDF11 expression, rescued its down-expression by siGDF11 and inhibit the adipogenesis of BMSCs cultured in high glucose medium. In vivo, liraglutide reversed the HFD-STZ induced excessive lipid droplets by up-regulation of GDF11 expression, which was discounted by agomiR-150-5p injection. Above all, liraglutide might alleviate bone marrow fat accumulation via inactivating miR-150-5p/GDF11 axis in diabetes.

Growth differentiation factor 11 regulates high glucose-induced cardiomyocyte pyroptosis and diabetic cardiomyopathy by inhibiting inflammasome activation.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with pyroptosis, a form of inflammation-related programmed cell death. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor ß superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating pyroptosis in DCM and the related mechanism. METHODS AND RESULTS: Mice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during pyroptosis was regulated by peroxisome proliferator-activated receptor α (PPARα). CONCLUSION: These findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection.

Functional analysis of a first hindlimb positioning enhancer via Gdf11 expression.

During the early development of tetrapods, including humans, the embryonic body elongates caudally once the anterior-posterior axis is established. During this process, region-specific vertebral morphogenesis occurs, with the determination of limb positioning along the anterior-posterior axis. We previously reported that Gdf11 functions as an anatomical integration system that determines the positioning of hindlimbs and sacral vertebrae where Gdf11 is expressed. However, the molecular mechanisms underlying induction of Gdf11 expression remain unclear. In this study, we searched for non-coding regions near the Gdf11 locus that were conserved across species to elucidate the regulatory mechanisms of Gdf11 expression. We identified an enhancer of the Gdf11 gene in intron 1 and named it highly conserved region (HCR). In HCR knockout mice, the expression level of endogenous Gdf11 was decreased, and the position of the sacral-hindlimb unit was shifted posteriorly. We also searched for factors upstream of Gdf11 based on the predicted transcription factor binding sites within the HCR. We found that inhibition of FGF signaling increased endogenous Gdf11 expression, suggesting that FGF signaling negatively regulates Gdf11 expression. However, FGF signaling does not regulate HCR activity. Our results suggest that there are species-specific Gdf11 enhancers other than HCR and that FGF signaling regulates Gdf11 expression independent of HCR.

Hapln1 promotes dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping.

Hyaluronan and proteoglycan link protein 1 (Hapln1) supports active cardiomyogenesis in zebrafish hearts, but its regulation in mammal cardiomyocytes is unclear. This study aimed to explore the potential regulation of Hapln1 in the dedifferentiation and proliferation of cardiomyocytes and its therapeutic value in myocardial infarction with human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and an adult mouse model of myocardial infarction. HiPSC-CMs and adult mice with myocardial infarction were used as in vitro and in vivo models, respectively. Previous single-cell RNA sequencing data were retrieved for bioinformatic exploration. The results showed that recombinant human Hapln1 (rhHapln1) promotes the proliferation of hiPSC-CMs in a dose-dependent manner. As a physical binding protein of Hapln1, versican interacted with Nodal growth differentiation factor (NODAL) and growth differentiation factor 11 (GDF11). GDF11, but not NODAL, was expressed by hiPSC-CMs. GDF11 expression was unaffected by rhHapln1 treatment. However, this molecule was required for rhHapln1-mediated activation of the transforming growth factor (TGF)-ß/Drosophila mothers against decapentaplegic protein (SMAD)2/3 signaling in hiPSC-CMs, which stimulates cell dedifferentiation and proliferation. Recombinant mouse Hapln1 (rmHapln1) could induce cardiac regeneration in the adult mouse model of myocardial infarction. In addition, rmHapln1 induced hiPSC-CM proliferation. In conclusion, Hapln1 can stimulate the dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping and subsequent activation of the TGF-ß/SMAD2/3 signaling pathway. Hapln1 might be an effective hiPSC-CM dedifferentiation and proliferation agent and a potential reagent for repairing damaged hearts.

GDF11: An emerging therapeutic target for liver diseases and fibrosis.

Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11 (BMP11), has been identified as a key player in various biological processes, including embryonic development, aging, metabolic disorders and cancers. GDF11 has also emerged as a critical component in liver development, injury and fibrosis. However, the effects of GDF11 on liver physiology and pathology have been a subject of debate among researchers due to conflicting reported outcomes. While some studies suggest that GDF11 has anti-aging properties, others have documented its senescence-inducing effects. Similarly, while GDF11 has been implicated in exacerbating liver injury, it has also been shown to have the potential to reduce liver fibrosis. In this narrative review, we present a comprehensive report of recent evidence elucidating the diverse roles of GDF11 in liver development, hepatic injury, regeneration and associated diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis and hepatocellular carcinoma. We also explore the therapeutic potential of GDF11 in managing various liver pathologies.

Progress in the relationship between GDF11 and depression.

Annually, the frequency of morbidity in depression has increased progressively in response to life stressors, and there is an increasing trend toward younger morbidity. The pathogenesis of depression is complicated and includes factors such as genetic inheritance and variations in physiological functions induced by various environmental factors. Currently, drug therapy has wide adaptability in clinical practice and plays an important role in the treatment of patients with mild depression. However, the therapeutic effects of most antidepressants are typically not significant and are associated with considerable adverse effects and addiction. Therefore, it is imperative to identify the deeper mechanisms of depression and search for alternative drug targets. Growth differentiation factor 11 (GDF11) is described as an anti-ageing molecule that belongs to a member of the transforming growth factor ß family. Additionally, the latest research findings suggested that GDF11 positively regulates neurogenesis and enhances neuronal activity, thereby attenuating depression-like behaviours. Although an increasing number of studies have focused on the multiple functions of GDF11 in skeletal dysplasia and carcinogenesis, its precise mechanism of action in depression remains unknown. Thus, in this review, we discuss the role of GDF11 and its mechanistic pathways in the pathogenesis of depression to develop novel therapies for depression.

Growth differentiation factor-11 upregulates matrix metalloproteinase 2 expression by inducing Snail in human extravillous trophoblast cells.

The human extravillous trophoblast (EVT) cell invasion is an important process during placentation. Although the placenta is normal tissue, the EVT cells exhibit some features common to cancer cells, including high migratory and invasive properties. Snail and Slug are transcription factors that mediate the epithelial-mesenchymal transition (EMT), a crucial event for cancer cell migration and invasion. It has been shown that GDF-11-induced matrix metalloproteinase 2 (MMP2) expression is required for EVT cell invasion. Whether GDF-11 can regulate Snail and Slug expression in human EVT cells remains unknown. If it does, the involvement of Snail and Slug in GDF-11-induced MMP2 expression and EVT cell invasion must also be defined. In the present study, using the immortalized human EVT cell line, HTR-8/SVneo, and primary cultures of human EVT cells as experimental models, our results show that GDF-11 upregulates Snail and Slug expression. ALK4 and ALK5 mediate the stimulatory effects of GDF-11 on Snail and Slug expression. In addition, we demonstrate that SMAD2 and SMAD3 are required for the GDF-11-upregulated Snail expression, while only SMAD3 is involved in GDF-11-induced Slug expression. Moreover, our results reveal that Snail mediates GDF-11-induced MMP2 expression and cell invasion but not Slug. This study increases our understanding of the biological function of GDF-11 in human EVT cells and provides a novel mechanism for regulating MMP2 and EVT cell invasion.

GDF11 level and its effect on prognosis in patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the proliferation of CD34 positive self-renewing malignant hematopoietic stem cells. Previous studies have shown that the transforming growth factor beta (TGFß) pathway plays a role in AML pathogenesis, especially by affecting the microenvironment. Growth differentiation factor 11 (GDF11) is a member of the TGFß superfamily, involved in embryological development and known as rejuvenating factor. In this study, our aim was to determine the serum GDF11 level in patients with AML, to compare it with the control group, to determine its relationship with follistatin, vimentin, and E-cadherin levels, and to determine whether GDF11 influences AML prognosis. Serum GDF11, vimentin, follistatin, and E-cadherin levels of newly diagnosed or relapsed/refractory AML patients and age- and gender-matched control group were measured by enzyme-linked immunosorbent assay. Serum GDF11 level was higher in the patient group (263.87 ± 126.54 ng/L) compared to the control group (211.54 ± 61.47 ng/L; p = 0.035). GDF11 level did not change according to age, gender, hemoglobin level, and bone marrow blast rate. No correlation was found between GDF11 level, response rates, and survival status of the patients. A positive correlation was detected between GDF11, E-cadherin, and vimentin levels. As a conclusion, increased serum GDF11 levels in AML patients may be linked to the regeneration ability of leukemic stem cells. There is a need for studies investigating GDF11 expression in myeloblasts.

The Effect of Liraglutide on Axon Regeneration and Functional Recovery after Peripheral Nerve Lesion.

Peripheral nerve injuries inflict severe consequences, necessitating innovative therapeutic strategies. This study investigates the potential of liraglutide, a glucagon-like peptide-1 receptor agonist, in mitigating the consequences of peripheral nerve injury. The existing treatment methods for such injuries underscore the importance of ongoing translational research efforts. Thirty adult Wistar rats underwent sciatic nerve dissection and repair surgery. The nerves were surgically transected using micro scissors at a precise location located 1.5 cm proximal to the trifurcation site. The study included a control group and two experimental groups, one treated with saline (placebo group) and the other with liraglutide (experimental group) for 12 weeks. Motor function, electromyography (EMG), and biochemical and histopathological analyses were performed after 12 weeks of treatment. Electrophysiological assessments revealed that liraglutide improved the compound muscle action potential (CMAP) amplitude and motor function compared to the saline-treated group. Histological and immunohistochemical analyses demonstrated increased NGF expression, total axon number, and diameter and reduced fibrosis in the liraglutide group. Biochemical analyses illustrated liraglutide's antioxidative properties, evidenced by reduced malondialdehyde (MDA) levels. Galectin-3 levels were suppressed and GDF-11 levels were modulated by liraglutide, indicating anti-inflammatory and anti-apoptotic effects. Liraglutide is a promising therapeutic intervention for peripheral nerve injuries, promoting functional recovery and histopathological improvement. Its multifaceted positive impact, beyond glycemic control, suggests constructive effects on the acute and chronic inflammatory processes associated with peripheral neuropathy. These findings warrant further research to elucidate molecular mechanisms and facilitate clinical translation. The study contributes valuable insights to the growing understanding of GLP-1 receptor agonists' neuroprotective properties in the context of peripheral nerve injuries.

The Influence of Metabolic Syndrome on Potential Aging Biomarkers in Participants with Metabolic Syndrome Compared to Healthy Controls.

BACKGROUND: Biological aging is a physiological process that can be altered by various factors. The presence of a chronic metabolic disease can accelerate aging and increase the risk of further chronic diseases. The aim of the study was to determine whether the presence of metabolic syndrome (MetS) affects levels of markers that are associated with, among other things, aging. MATERIAL AND METHODS: A total of 169 subjects (58 with MetS, and 111 without metabolic syndrome, i.e., non-MetS) participated in the study. Levels of telomerase, GDF11/15, sirtuin 1, follistatin, NLRP3, AGEs, klotho, DNA/RNA damage, NAD+, vitamin D, and blood lipids were assessed from blood samples using specific enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: Telomerase (p < 0.01), DNA/RNA damage (p < 0.006) and GDF15 (p < 0.02) were higher in MetS group compared to non-MetS group. Only vitamin D levels were higher in the non-MetS group (p < 0.0002). Differences between MetS and non-MetS persons were also detected in groups divided according to age: in under 35-year-olds and those aged 35-50 years. CONCLUSIONS: Our results show that people with MetS compared to those without MetS have higher levels of some of the measured markers of biological aging. Thus, the presence of MetS may accelerate biological aging, which may be associated with an increased risk of chronic comorbidities that accompany MetS (cardiovascular, inflammatory, autoimmune, neurodegenerative, metabolic, or cancer diseases) and risk of premature death from all causes.

The regulatory effect of growth differentiation factor 11 on different cells.

Growth differentiation factor 11 (GDF11) is one of the important factors in the pathophysiological process of animals. It is widely expressed in many tissues and organs of animals, showing its wide biological activity and potential application value. Previous research has demonstrated that GDF11 has a therapeutic effect on various diseases, such as anti-myocardial aging and anti-tumor. This has not only sparked intense interest and enthusiasm among academics but also spurred some for-profit businesses to attempt to develop GDF11 as a medication for regenerative medicine or anti-aging application. Currently, Sotatercept, a GDF11 antibody drug, is in the marketing application stage, and HS-235 and rGDF11 are in the preclinical research stage. Therefore, we believe that figuring out which cells GDF11 acts on and its current problems should be an important issue in the scientific and commercial communities. Only through extensive, comprehensive research and discussion can we better understand the role and potential of GDF11, while avoiding unnecessary risks and misinformation. In this review, we aimed to summarize the role of GDF11 in different cells and its current controversies and challenges, providing an important reference for us to deeply understand the function of GDF11 and formulate more effective treatment strategies in the future.

GDF11 and aging biology - controversies resolved and pending.

Since the exogenous administration of GDF11, a TGF-ß superfamily member, was reported to have beneficial effects in some models of human disease, there have been many research studies in GDF11 biology. However, many studies have now confirmed that exogenous administration of GDF11 can improve physiology in disease models, including cardiac fibrosis, experimental stroke, and disordered metabolism. GDF11 is similar to GDF8 (also called Myostatin), differing only by 11 amino acids in their mature signaling domains. These two proteins are now known to be biochemically different both in vitro and in vivo. GDF11 is much more potent than GDF8 and induces more strongly SMAD2 phosphorylation in the myocardium compared to GDF8. GDF8 and GDF11 prodomain are only 52% identical and are cleaved by different Tolloid proteases to liberate the mature signaling domain from inhibition of the prodomain. Here, we review the state of GDF11 biology, highlighting both resolved and remaining controversies.

Comparative evaluation of rhFGF18 and rhGDF11 treatment in a transient ischemia stroke model.

Background: Pharmacological treatments for ischemic stroke remain limited to thrombolysis, which is associated with increased risk of potentially fatal hemorrhage. Treatments with Recombinant Human Fibroblast Growth Factor 18 (rhFGF18) and Growth and Differentiation Factor 11 (rhGDF11) appear promising based on different preclinical models. The goal of this study was to compare the effects of rhFGF18 and rhGDF11 directly on survival, behavioral deficits, and histological fingerprint of cerebral ischemia in the Wistar rat middle cerebral artery occlusion (MCAO) model of stroke. Methods: Ischemia-reperfusion injury was induced using a 2-hour transient MCAO. Animals were administered rhFGF18 (infusion), rhGDF11 (multi-injection), or Phosphate Buffered Saline (PBS) vehicle control and followed for 42 days. Motor-Cognitive deficits were evaluated using the Morris Water Maze at Days 0 (pre-MCAO), 7, 21, and 42. Histopathological assessments were performed on Days 21 and 42. Results: Day 7 post-ischemia water maze performance times increased 38.3%, 2.1%, and 23.1% for PBS, rhFGF18, and rhGDF11-treated groups, respectively. Fraction of neurons with abnormal morphology (chromatolysis, pyknotic nuclei, somal degeneration) decreased in all groups toward Day 42 and was lowest for rhFGF18. AChE-positive fiber density and activity increased over time in the rhFGF18 group, remained unchanged in the rhGDF11 treatment arm, and declined in the PBS control. Metabolic increases were greatest in rhGDF11 treated animals, with both rhFGF18 and rhGDF11 achieving improvements over PBS, as evidenced by increased succinate dehydrogenase and lactate dehydrogenase activity. Finally, rhFGF18 treatment exhibited a trend for reduced mortality relative to PBS (5.6%, 95% CI [27.3%, 0.1% ] vs. 22.2%, 95% CI [47.6%, 6.4% ]). Conclusions: rhFGF18 treatment appears promising in improving survival and promoting motor-cognitive recovery following cerebral ischemia-reperfusion injury.

Protective effects of growth differentiation factor 11 on β-cell function in db/db diabetic mice and its possible mechanism / 中华内分泌代谢杂志

Objective To investigate the effects of growth differentiation factor 11 ( GDF11 ) on β-cell function in db/db mice and its possible mechanism. Methods Twenty eight-week-old male db/db mice were randomizedtoi.p. administration of GDF11(0.3mg·kg-1·day-1)or equivalent PBS(n=10)for 6 weeks.10age-matched male db/m were used as normal control, received equivalent PBS injection for 6 weeks. Blood glucose levels, body weights and food intake were monitored weekly. IPGTT and glucose-stimulated insulin secretion ( GSIS) were analyzed. After 6 weeks of intervention, serum HbA1C , TG, TC, and FFA were measured respectively. The concentrations of hormones in serum and pancreas were evaluated. The mRNA expression of Pdx-1, MafA, Nkx6. 1, and insulin2 were determined by RT-PCR. The expression of phosphorylated Smd2 (P-Smad2), Smad2 in islet were examined by western blot. Results Compared with NC group, GDF11 administration decreased FBG, HbA1C , modified lipid profiles. GDF11 improved glucose tolerance and augmented GSIS. Moreover, GDF11 increased serum insulin and pancreatic insulin content, while decreased serum glucagon concentration. The expression of Pdx-1, MafA, Nkx6. 1, and Insulin2 were significantly increased in GDF11 group. GDF11 elevated the expression of P-Smad2 in islets. Conclusion s GDF11 may preserve β-cell function and facilitate the secretion and production of insulin. Diminishing the metabolic abnormalities, alleviating the secretion of glucagon, as well as maintaining the key transcript factor activation may contribute to the amelioration of β-cell function after GDF11 administration. Smad2 pathway may be related to the protective effects of GDF11.

Role of GDF11 in skeletal muscle cell insulin resistance induced by palmitate / 中国药理学通报

Aim To investigate the role of GDF11 in palmitate induced skeletal muscle insulin resistance.Methods The C2C12 cells were sorted into control group, GDF11 intervention group, palmitate group and GDF11 combined with palmitate group.Cell viability was measured by CCK-8, and the glucose uptake was determined by 2NBDG.The mRNA level of myotube marker genes(desmin,myogenin), insulin mediate glucose uptake related genes(GLUT-4,IRS-1) and PGC-1α were tested by RT-PCR.The protein expression of PGC-1α was detected by western blot.Results GDF11 had little effect on cell viability of skeletal muscle cells.Compared with control group, the glucose uptake and the expression of GLUT-4,IRS-1,PGC-1α were significantly decreased by palmitate intervention.Compared with palmitate group, the glucose uptake and the expression of GLUT-4,IRS-1,PGC-1α were not significantly changed by GDF11.Conclusion Palmitate can induce skeletal muscle cell insulin resistance, but GDF11 may not significantly improve the skeletal muscle cell insulin resistance.