Fibronectin Type III Domain-containing Protein 5 Research Articles

The role and underlying mechanisms of irisin in exercise-mediated cardiovascular protection.

Irisin, a product of the post-translational processing of fibronectin type III domain-containing protein 5 (FNDC5), is a novel myokine which is upregulated during exercise. This hormone not only promotes the transformation of white adipose tissue into a brown-fat-like phenotype but also enhances energy expenditure and mitigates fat accumulation. Its role is crucial in the management of certain metabolic disorders such as diabetes and heart disease. Of note, the type of exercise performed significantly affects blood irisin levels, indicating the critical role of physical activity in regulating this hormone. This article aims to summarize the current scientific understanding of the role of irisin and the mechanisms through which it mediates cardiovascular protection through exercise. Moreover, this article aims to establish irisin as a potential target for preventing and treating cardiovascular diseases.

Exercise Promotes Hippocampal Neurogenesis in T2DM Mice via Irisin/TLR4/MyD88/NF-κB-Mediated Neuroinflammation Pathway.

Neuroinflammation is a major feature of type 2 diabetic mellitus (T2DM), adversely affecting hippocampal neurogenesis. However, the precise mechanism is not fully understood, and therapeutic approaches are currently lacking. Therefore, we determined the effects of exercise on neuroinflammation and hippocampal neurogenesis in T2DM mice, with a specific focus on understanding the role of the irisin and related cascade pathways in modulating the beneficial effects of exercise in these processes. Ten-week exercise significantly decreased T2DM-induced inflammation levels and markedly promoted hippocampal neurogenesis and memory function. However, these positive effects were reversed by 10 weeks of treatment with cyclo RGDyk, an inhibitor of irisin receptor signaling. Additionally, exercise helped reduce the M1 phenotype polarization of hippocampal microglia in diabetic mice; this effect could be reversed with cyclo RGDyk treatment. Moreover, exercise markedly increased the levels of fibronectin type III domain-containing protein 5 (FNDC5)/irisin protein while decreasing the expression of Toll-like receptor 4 (TLR4), myeloid differential protein-88 (MyD88), and nuclear factor kappa-B (NF-κB) in the hippocampus of T2DM mice. However, blocking irisin receptor signaling counteracted the down-regulation of TLR4/MyD88/NF-κB in diabetic mice undergoing exercise intervention. Conclusively, exercise appears to be effective in reducing neuroinflammation and enhancing hippocampal neurogenesis and memory in diabetes mice. The positive effects are involved in the participation of the irisin/TLR4/MyD88/NF-κB signaling pathway, highlighting the potential of exercise in the management of diabetic-induced cognitive decline.

Differential mitochondrial adaptation and FNDC5 production in brown and white adipose tissue in response to cold and obesity.

Fibronectin type III domain-containing protein 5 (FNDC5) modulates adipocyte metabolism by increasing white and brown adipose tissue (WAT and BAT) browning and activity, respectively. We investigated whether FNDC5 can regulate visceral WAT and BAT adaptive thermogenesis by improving mitochondrial homeostasis in response to cold and obesity. Adipose tissue expression of FNDC5 and factors involved in mitochondrial homeostasis were determined in patients with normal weight and obesity (n = 159) and in rats with diet-induced obesity after 1 week of cold exposure (n = 61). The effect of different FNDC5 concentrations on mitochondrial biogenesis, dynamics, and mitophagy was evaluated in vitro in human adipocytes. In human visceral adipocytes, FNDC5/irisin triggered mitochondrial biogenesis (TFAM) and fusion (MFN1, MFN2, and OPA1) while inhibiting peripheral fission (DNM1L and FIS1) and mitophagy (PINK1 and PRKN). Circulating and visceral WAT expression of FNDC5 wasdecreased in patients and experimental animals with obesity, whereas its receptor, integrin αV, was upregulated. Obesity increased mitochondrial fusion while decreasing mitophagy in visceral WAT from patients and rats. By contrast, in rat BAT, an upregulation of Fndc5 and genes involved in mitochondrial biogenesis and fission was observed. Cold exposure promoted mitochondrial biogenesis and healthy peripheral fission while repressing Fndc5 expression and mitophagy in BAT from rats. Depot differences in FNDC5 production and mitochondrial adaptations in response to obesity and cold might indicate a self-regulatory mechanism to control thermogenesis in response to energy needs.

FNDC5 IS THE KEY MOLECULE TO INHIBIT MUSCLE FIBER DEVELOPMENT IN TIBETAN PIGS

Differences in muscle fiber development between Tibetan and Yorkshire pigs determine their performance in terms of meat quality, taste, and food value. To investigate the molecular regulation of muscle fiber development by fibronectin type III domain-containing protein 5 (FNDC5), a preliminary study of FNDC5 gene expression in the longissimus dorsi muscle and Leg muscle tissues of Tibetan and Yorkshire Pigs was conducted using RT–qPCR and western blotting. Muscle tissues were sectioned and stained to observe the muscle fiber diameter and area under a microscope. The mRNA and protein expression levels of FNDC5, and the diameter and area of muscle fibers in the longissimus dorsi muscle and Leg muscle tissues of Tibetan pigs were significantly lower than those in Yorkshire Pigs. The results imply that FNDC5 negatively regulates muscle fiber diameter in pigs. The role of FNDC5 in pork quality has important implications for improving pork production efficiency, pork quality, and the sustainable development of the livestock industry. Keywords: Pig; FNDC5; Gene expression.

Swimming alleviates myocardial fibrosis of type II diabetic rats through activating miR-34a-mediated SIRT1/PGC-1α/FNDC5 signal pathway.

Myocardial fibrosis can trigger heart failure in diabetic cardiomyopathy (DCM), and irisin, an exercise-induced myokine, may have a beneficial effect on cardiac function. However, the specific molecular mechanism between exercise and irisin in the diabetic heart remains not fully explored. This study aimed to investigate how miR-34a mediates exercise-induced irisin to ameliorate myocardial fibrosis and its underlying mechanisms. Type 2 diabetes mellitus (T2DM) with DCM was induced in adult male rats with high-fat diet and streptozotocin injection. The DCM rats were subjected to swimming (60 min/d) and recombinant irisin (r-irisin, 500 μg/kg/d) interventions for 8 weeks, respectively. Cardiac function, cardiomyocyte structure, myocardial fibrosis and its correlated gene and protein expression were analyzed. Swimming intervention alleviated insulin resistance, myocardial fibrosis, and myocardial hypertrophy, and promoted blood glucose homeostasis in T2DM model rats. This improvement was associated with irisin upregulation and miR-34a downregulation in the myocardium, thus enhancing cardiac function. Similar efficacy was observed via intraperitoneal injection of exogenous recombinant irisin. Inhibition of miR-34a in vivo exhibited an anti-myocardial fibrotic effect by promoting irisin secretion through activating sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α)/fibronectin type III domain-containing protein 5 (FNDC5) signal pathway and downregulating myocardial fibrosis markers (collagen I, collagen III, and transforming growth factor-β1). Therefore, swimming-induced irisin has the potential therapeutic effect on diabetic myocardial fibrosis through activating the miR-34a-mediated SIRT1/PGC-1α/FNDC5 signal pathway.

Effects of Aerobic Exercise and Resistance Training on Cognitive Function: Comparative Study Based on FNDC5/Irisin/BDNF Pathway

Introduction: Exercise has been recommended to suppress or prevent cognitive decline. Aerobic exercise (AE) may suppress cognitive decline via the fibronectin type III domain-containing protein 5 (FNDC5)/irisin/brain-derived neurotrophic factor (BDNF) pathway, and resistance training (RT) has a preventive effect on cognitive decline. However, the underlying mechanism remains unclear. This study verified the differences in the effects of AE and RT in suppressing and preventing cognitive decline based on the FNDC5/irisin/BDNF pathway. Methods: We divided senescence-accelerated mouse-prone 8 into three groups: control (CON), AE, and RT and evaluated their memory during exercise intervention through a novel object recognition (NOR) task. We quantified FNDC5/irisin, mBDNF, and TrkB in the hippocampus using enzyme-linked immunosorbent assay and FNDC5 in skeletal muscle using Western blotting (WB). Results: Behavioral analysis using NOR showed that values for both AE and RT were significantly greater than those for CON. WB analysis showed that the peripheral FNDC5 expression in the skeletal muscle was increased in AE. The expression levels of FNDC5/irisin and mBDNF in the hippocampus were significantly increased in both AE and RT compared with that in CON but that if TrkB was increased only in AE. Conclusion: No significant difference was observed between AE and RT in the inhibitory effect on age-related cognitive decline, and both groups were effective. The FNDC5/Irisin/BDNF pathway, which was the focus of this experiment, may be specific to AE. The mechanism that suppresses cognitive decline may differ depending on the type of exercise.

ELK4 ameliorates cognitive impairment and neuroinflammation induced by obstructive sleep apnea

Intermittent hypoxia (IH) in patients with obstructive sleep apnea (OSA) syndrome elicited neuron injury (especially in the hippocampus and cortex), contributing to cognitive dysfunction. This study investigated the effects and clarified the mechanisms of ETS domain-containing protein Elk-4 (ELK4) on the cognitive function and neuroinflammation of mice with IH. Mouse microglia BV2 cells were induced with IH by exposure to fluctuating O2 concentrations (alternating from 5 % to 21 % every 30 min), and mice with OSA were developed and subjected to lentivirus-mediated gene intervention. ELK4 expression was significantly reduced in IH-induced microglia and brain tissues of mice with OSA. Overexpression of ELK4 attenuated oxidative stress, decreased the pro-inflammatory factors IL-1β, IL-6, and TNF-α, and increased the level of the anti-inflammatory factors IL-10 and TGF-β1, as well as the neuroprotective factor BDNF. ELK4 promoted the transcription of fibronectin type III domain-containing protein 5 (FNDC5) by binding to the promoter of FNDC5. Knockdown of FNDC5 in IH-induced microglia and animals reversed the protective effects of ELK4 on OSA-associated neuroinflammation and cognitive dysfunction. Overall, the results demonstrated that ELK4 overexpression repressed microglial activation by inducing the transcription of FNDC5, thus attenuating neuroinflammation and cognitive dysfunction induced by OSA.

Reduced FNDC5-AMPK signaling in diabetic atrium increases the susceptibility of atrial fibrillation by impairing mitochondrial dynamics and activating NLRP3 inflammasome

Fibronectin type III domain-containing protein 5 (FNDC5) exerts potential anti-arrhythmic effects. However, the function and mechanism of FNDC5 in diabetes-associated atrial fibrillation (AF) remain unknown. In this study, bioinformatics analysis, in vivo and in vitro experiments were conducted to explore the alteration and role of FNDC5 in diabetes-related atrial remodeling and AF susceptibility. RNA sequencing data from atrial samples of permanent AF patients and diabetic mice exhibited significantly decreased FNDC5 at the transcriptional level, which was in line with the protein expression in diabetic mice as well as high glucose and palmitic acid (HG+PA) injured atrial myocytes. Diabetic mice exhibited adverse atrial remodeling and increased AF inducibility. Moreover, reduced atrial FNDC5 was accompanied with exacerbated NOD-like receptor pyrin domain containing 3 (NLRP3) activation and disturbed mitochondrial fission and fusion processes, as evidenced by decreased expressions of optic atrophy 1 (OPA-1), mitofusin (MFN-1, MFN-2) and increased phosphorylation of dynamin-related protein 1 (Ser616). These effects were validated in HG+PA-treated atrial myocytes. Critically, FNDC5 overexpression remarkably enhanced cellular antioxidant capacity by upregulating the expressions of superoxide dismutase (SOD1, SOD2) level. In addition, HG+PA-induced mitochondrial dysfunction was ameliorated by FNDC5 overexpression as evidenced by improved mitochondrial dynamics and membrane potential. Moreover, NLRP3 inflammasome-mediated inflammation was reduced by FNDC5 overexpression, and AMPK signaling might serve as the key down-stream effector. The present study demonstrated that reduced atrial FNDC5-AMPK signaling contributed to the pathogenesis of diabetes- associated AF by impairing mitochondrial dynamics and activating the NLRP3 inflammasome. These findings provide promising therapeutic avenues for diabetes-associated AF.

Diet Based on Pereskia aculeata Miller Flour Increases Muscle Volume and Modulates the Expression of Myokines in Mice Subjected to Resistance Training.

The study aimed to evaluate the effects of Pereskia aculeata Miller (ora-pro-nobis [OPN]) flour on body and biochemical parameters, thermogenic activity, and molecular expression of markers in the muscle tissue of mice subjected to resistance training (RT). Twelve mice were randomly assigned to two groups (n=6 animals/group): G1: control (Control) fed a standard diet + RT and G2: experimental (OPN) fed a diet based on OPN flour + RT. The RT consisted of a 6-week program using a vertical ladder combined with a fixed weight attached to the animal. Several parameters were measured, including assessment of body composition, biochemical markers, thermogenic activity, and molecular (mRNA expression of interleukin (IL)-6, fibronectin type III domain-containing protein 5 (FNDC5), peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), nuclear respiratory factor 1 (NRF1), and mitochondrial transcription factor A (TFAM). The OPN group exhibited a decrease in body weight and visceral adiposity, higher energy expenditure, and lipid oxidation rate. In addition, it was observed an increase in muscle volume and in mRNA expression levels of IL-6, FNDC5, PGC-1α, and TFAM. These findings suggest that OPN flour could be a nutritional option to enhance performance in RT.

Therapeutic potential of exercise-hormone irisin in Alzheimer's disease.

Irisin is a myokine that is generated by cleavage of the membrane protein fibronectin type III domain-containing protein 5 (FNDC5) in response to physical exercise. Studies reveal that irisin/FNDC5 has neuroprotective functions against Alzheimer's disease, the most common form of dementia in the elderly, by improving cognitive function and reducing amyloid-β and tau pathologies as well as neuroinflammation in cell culture or animal models of Alzheimer's disease. Although current and ongoing studies on irisin/FNDC5 show promising results, further mechanistic studies are required to clarify its potential as a meaningful therapeutic target for alleviating Alzheimer's disease. We recently found that irisin treatment reduces amyloid-β pathology by increasing the activity/levels of amyloid-β-degrading enzyme neprilysin secreted from astrocytes. Herein, we present an overview of irisin/FNDC5's protective roles and mechanisms against Alzheimer's disease.

The Application Potential of the Regulation of Tregs Function by Irisin in the Prevention and Treatment of Immune-Related Diseases.

Irisin is a muscle factor induced by exercise, generated through the proteolytic cleavage of the membrane protein fibronectin type III domain-containing protein 5 (FNDC-5). Numerous studies have shown that irisin plays a significant role in regulating glucose and lipid metabolism, inhibiting oxidative stress, reducing systemic inflammatory responses, and providing neuroprotection. Additionally, irisin can exert immunomodulatory functions by regulating regulatory T cells (Tregs). Tregs are a highly differentiated subset of mature T cells that play a key role in maintaining self-immune homeostasis and are closely related to infections, inflammation, immune-related diseases, and tumors. Irisin exerts persistent positive effects on Treg cell functions through various mechanisms, including regulating Treg cell differentiation and proliferation, improving their function, modulating the balance of immune cells, increasing the production of anti-inflammatory cytokines, and enhancing metabolic functions, thereby helping to maintain immune homeostasis and prevent immune-related diseases. As an important myokine, irisin interacts with receptors on the cell membrane, activating multiple intracellular signaling pathways to regulate cell metabolism, proliferation, and function. Although the specific receptor for irisin has not been fully identified, integrins are considered potential receptors. Irisin activates various signaling pathways, including AMPK, MAPK, and PI3K/Akt, through integrin receptors, thereby exerting multiple biological effects. These research findings provide important clues for understanding the mechanisms of irisin's action and theoretical basis for its potential applications in metabolic diseases and immunomodulation. This article reviews the relationship between irisin and Tregs, as well as the research progress of irisin in immune-related diseases such as multiple sclerosis, myasthenia gravis, acquired immune deficiency syndrome, type 1 diabetes, sepsis, and rheumatoid arthritis. Studies have revealed that irisin plays an important role in immune regulation by improving the function of Tregs, suggesting its potential application value in the treatment of immune-related diseases.

Changes in apoptosis and adipokine biomarkers in the heart tissue of rats with experimental hyperthyroidism

Background and purpose: This study aimed to investigate the effects of hyperthyroidism on heart tissue through adipokines and apoptotic signalling pathways. Materials and Methods: A total of 14 Sprague-Dawley male rats were assigned to 2 groups, a control and a hyperthyroid group. The control group received 0.9% NaCl, while the hyperthyroid group received 1 mg/kg levothyroxine dissolved in 0.9% NaCl throughout the study. Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels in serum samples, whereas fibronectin type III domain-containing protein 5 (FNDC5), adiponectin, B-cell lymphoma-2 (Bcl-2) and tumour protein 53 (p53) levels in heart tissue were determined by ELISA method. Results: Serum TSH level decreased (p<0.01) while the level of FT4 significantly (p<0.01) increased in the hyperthyroid group compared to the control group. The level of adiponectin in the cardiac tissue of levothyroxinetreated rats was found to be significantly higher than in the control group (p<0.01). Additionally, compared to the control group, the antiapoptotic Bcl-2 level increased (p<0.05) while the proapoptotic p53 level decreased in the hyperthyroid group (p<0.01). Conclusions: In this study, the effects of hyperthyroidism on hormone levels, which are important regulators of energy and metabolic homeostasis, and changes in apoptosis markers were revealed in heart tissue. We consider that apoptosis was potentially prevented by activating mechanisms in order to protect cardiac functions in the beginning, but this scene may be reversed in progressive hyperthyroidism cases. Therefore, their pathways need to be supported by more detailed and time-compared studies.

Fibronectin type III domain-containing protein 5 (FNDC5)-like immunoreactivity and mRNA abundance in domestic animal tissues

Irisin is a 112-amino acid peptide hormone that is cleaved from fibronectin type III domain-containing protein 5 (FNDC5), a type I transmembrane protein abundantly found in muscle tissue. Irisin is a putative mediator of the benefits of exercise, neuroprotection, bone growth, and cardiac health. However, few studies have focused on irisin in domestic animals. Further, whether processed irisin is detectable in domestic animal tissues remains uncertain. To address this, we determined FNDC5 mRNA and protein concentration in anatine (duck) and porcine (pig) skeletal muscle, and in equine (horse), swine, and anatine serum samples. RT-PCR analysis identified FNDC5 mRNA in all pig and duck skeletal muscle samples. An approximately 25 kDa band representing FNDC5 was detected in both pig and duck skeletal muscle. Fluorescence immunohistochemistry using a rabbit monoclonal FNDC5/irisin primary antibody and a goat polyclonal anti-rabbit secondary antibody localized FNDC5/irisin-like immunoreactivity in both the glandular and muscular regions of pig stomach. FNDC5/irisin-like immunoreactivity was also identified in horse, pig, and duck serum using a multispecies irisin ELISA. The average values of irisin-like immunoreactivity were 13.7 (duck), 15.4 (horse), and 7.0 (pig) ng/mL in samples tested. Our results support the presence of irisin precursor in several domestic animals. Processed irisin, however, was not detectable. Further studies are required to validate reliable tools to detect and quantify processed irisin in domestic animals.

Astragaloside IV inhibits angiotensin II-induced atrial fibrosis and atrial fibrillation by SIRT1/PGC-1α/FNDC5 pathway

Aims and objectivesAstragaloside IV (AS-IV) has been found to possess anti-oxidative, anti-inflammatory, and anti-apoptotic properties, but its effect on atrial fibrosis is yet to be determined. This research investigates the protective role of AS-IV in angiotensin II (Ang II)-induced atrial fibrosis and atrial fibrillation (AF). MethodsC57BL/6 male mice aged 8–10 weeks (n = 40) were subcutaneously administered Ang II (2.0 mg/kg/day) or saline, with AS-IV (80 mg/kg) intraperitoneally administered 2 h before Ang II infusion for 4 weeks. Biochemical, histological, and morphological analyses were carried out. Using transesophageal burst pacing, AF was generated in vivo. ResultsHere, we report that AS-IV treatment inhibited Ang II-induced AF development in mice (58 ± 5.86 vs 15.13 ± 2.16 %, p < 0.001). Ang II + AS-IV therapy was effective in reducing the atrial fibrotic area and decreasing the increase in smooth muscle alpha-actin (α-SMA)-positive myofibroblasts brought on by Ang II treatment (fibrotic area: 26.25 ± 3.81 vs 8.62 ± 1.83 %, p < 0.001 and α-SMA: 65.62 ± 10.63 vs 17.25 ± 1.78 %, p < 0.001). The reactive oxygen species (ROS) production was reduced by pretreatment with Ang II + AS-IV (9.20 ± 0.92 vs 2.63 ± 0.22 %/sec, p < 0.001). In addition, Ang II + AS-IV treatment suppressed oxidative stress in Ang II-induced atrial fibrosis (malondialdehyde: 701.78 ± 85.01 vs 504.07 ± 25.62 pmol/mg protein, p < 0.001; superoxide dismutase: 13.82 ± 1.25 vs 29.54 ± 2.45 U/mg protein, p < 0.001 and catalase: 11.43 ± 1.19 vs 20.83 ± 3.29 U/mg protein, p < 0.001, respectively). Moreover, Ang II + AS-IV decreased the expression of α-SMA, collagen III and collagen I (3.32 ± 0.53 vs 1.41 ± 0.20 fold, p < 0.001; 3.41 ± 0.55 vs 1.48 ± 0.18 fold, p < 0.001; 2.34 ± 0.55 vs 0.99 ± 0.17 fold, p < 0.001, respectively) while increasing the protein expression of sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), and fibronectin type III domain-containing protein 5 (FNDC5) in Ang II-treated mice (0.22 ± 0.02 vs 0.57 ± 0.08 fold, p < 0.001; 0.28 ± 0.04 vs 0.72 ± 0.05 fold, p < 0.001; 0.38 ± 0.03 vs 0.68 ± 0.06 fold, p < 0.001, respectively). ConclusionOur data led us to speculate that AS-IV may protect against Ang II-induced atrial fibrosis and AF via upregulation of the SIRT1/PGC-1α/FNDC5 pathway.

Irisin, A Fascinating and Multifunctional Protein: Implication for Health

BACKGROUND: Fibronectin type III domain-containing protein 5 (FNDC5), or also known as irisin, has been identified for two decades but almost completely disregarded for 10 years. It is present in skeletal muscle, heart, and brain, and in reaction to exercise can transform white adipose tissue into brown. Since then, irisin has gained a lot of attention for its potencies in treating metabolic disorders. In this review article, the potential future of irisin especially on metabolism and aging process will be discussed.CONTENT: Sedentary lifestyle is acknowledged as risk factor for type 2 diabetes mellitus, obesity, immune system issues, asthma, and neurological or heart illness. Irisin is secreted by muscle cells when exercising, produced after the proteolytic cleavage of FNDC5 protein. Irisin has positive impacts on maintaining physiological balance including reducing inflammation, keeping the bone homeostasis, as well as influencing metabolic processes and the neurological system function. Due to these many and advantageous characteristics, irisin could be a possible choice for preventing and managing disorders associated with modern society, and finding the agents to increase irisin can be beneficial.SUMMARY: Irisin offers a fresh potential basis for kinesitherapy and shows promise as a therapeutic target due to its various biological activities. Irisin pathway can be activated through dietary changes, the use of natural substances and drugs and can interact with this signalling pathway which involved peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and uncoupling protein mRNA 1 (UCP1) to resolve obesity and its metabolic comorbidities.KEYWORDS: irisin, FNDC5, exercise, inflammation, obesity, nervous system

Hydrogen Sulfide and Irisin, Potential Allies in Ensuring Cardiovascular Health.

Irisin is a myokine secreted under the influence of physical activity and exposure to low temperatures and through different exogenous stimuli by the cleavage of its precursor, fibronectin type III domain-containing protein 5 (FNDC5). It is mainly known for maintaining of metabolic homeostasis, promoting the browning of white adipose tissue, the thermogenesis process, and glucose homeostasis. Growing experimental evidence suggests the possible central role of irisin in the regulation of cardiometabolic pathophysiological processes. On the other side, hydrogen sulfide (H2S) is well recognized as a pleiotropic gasotransmitter that regulates several homeostatic balances and physiological functions and takes part in the pathogenesis of cardiometabolic diseases. Through the S-persulfidation of cysteine protein residues, H2S is capable of interacting with crucial signaling pathways, exerting beneficial effects in regulating glucose and lipid homeostasis as well. H2S and irisin seem to be intertwined; indeed, recently, H2S was found to regulate irisin secretion by activating the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)/FNDC5/irisin signaling pathway, and they share several mechanisms of action. Their involvement in metabolic diseases is confirmed by the detection of their lower circulating levels in obese and diabetic subjects. Along with the importance of metabolic disorders, these modulators exert favorable effects against cardiovascular diseases, preventing incidents of hypertension, atherosclerosis, heart failure, myocardial infarction, and ischemia-reperfusion injury. This review, for the first time, aims to explore the role of H2S and irisin and their possible crosstalk in cardiovascular diseases, pointing out the main effects exerted through the common molecular pathways involved.

FNDC5 IS THE KEY MOLECULE TO INHIBIT MUSCLE FIBER DEVELOPMENT IN TIBETAN PIGS

Differences in muscle fiber development between Tibetan and Yorkshire pigs determine their performance in terms of meat quality, taste, and food value. To investigate the molecular regulation of muscle fiber development by fibronectin type III domain-containing protein 5 (FNDC5), a preliminary study of FNDC5 gene expression in the longissimus dorsi muscle and Leg muscle tissues of Tibetan and Yorkshire Pigs was conducted using RT–qPCR and western blotting. Muscle tissues were sectioned and stained to observe the muscle fiber diameter and area under a microscope. The mRNA and protein expression levels of FNDC5, and the diameter and area of muscle fibers in the longissimus dorsi muscle and Leg muscle tissues of Tibetan pigs were significantly lower than those in Yorkshire Pigs. The results imply that FNDC5 negatively regulates muscle fiber diameter in pigs. The role of FNDC5 in pork quality has important implications for improving pork production efficiency, pork quality, and the sustainable development of the livestock industry. Keywords: Pig; FNDC5; Gene expression.

FNDC5 inhibits malignant growth of human cervical cancer cells via restraining PI3K/AKT pathway.

Cervical cancer (CxCa) is the fourth most frequent cancer in women. This study aimed to determine the role and underlying mechanism of fibronectin type III domain-containing protein 5 (FNDC5) in inhibiting CxCa growth. Experiments were performed in human CxCa tissues, human CxCa cell lines (HeLa and SiHa), and xenograft mouse model established by subcutaneous injection of SiHa cells in nude mice. Bioinformatics analysis showed that CxCa patients with high FNDC5 levels have a longer overall survival period. FNDC5 expression was increased in human CxCa tissues, HeLa and SiHa cells. FNDC5 overexpression or FNDC5 protein not only inhibited proliferation, but also restrained invasion and migration of HeLa and SiHa cells. The effects of FNDC5 were prevented by inhibiting integrin with cilengitide, activating PI3K with recilisib or activating Akt with SC79. FNDC5 inhibited the phosphorylation of PI3K and Akt, which was attenuated by recilisib. PI3K inhibitor LY294002 showed similar effects to FNDC5 in HeLa and SiHa cells. Intravenous injection of FNDC5 (20 μg/day) for 14 days inhibited the tumor growth, and reduced the proliferation marker Ki67 expression and the Akt phosphorylation in the CxCa xenograft mouse model. These results indicate that FNDC5 inhibits the malignant phenotype of CxCa cells through restraining PI3K/Akt signaling. Upregulation of FNDC5 may play a beneficial role in retarding the tumor growth of CxCa.

Can SLU-PP-332 be a new drug to prevent COVID-19?

Given the fact that the forecasts show the continuation of the occurrence of cases of coronavirus disease 19 (COVID-19) and the evolution towards Long COVID, the identification of a chemoprophylactic agent is of major importance. For this purpose, we propose SLU-PP-332, an estrogen-related receptor alpha (ERRα) agonist, which, besides the effect of stimulating mitochondrial biogenesis, it is possible to inhibit angiotensin-converting enzyme 2 (ACE2), stimulate immunity, inhibit pro-inflammatory cytokines, reduce the number of entry points into cells of SARS-CoV-2 at the level of adipose tissue through fibronectin type III domain-containing protein 5 (FNDC5), and to protect vascular endothelium from oxidative stress. Considering the existence of experimental models for COVID-19, it is possible to test these effects, as well as the possibility of combining the administration of SLU-PP-332 with the performance of moderate-intensity physical exercises, this in order to accelerate the adaptation to exercise of the mitochondria of the whole body, a supposed prophylactic factor for severe forms of COVID-19.

FNDC5/irisin ameliorates bone loss of type 1 diabetes by suppressing endoplasmic reticulum stress‑mediated ferroptosis

BackgroundFerroptosis is known to play a crucial role in diabetic osteopathy. However, key genes and molecular mechanisms remain largely unclear. This study aimed to identify a crucial ferroptosis-related differentially expressed gene (FR-DEG) in diabetic osteopathy and investigate its potential mechanism.MethodsWe identified fibronectin type III domain-containing protein 5 (FNDC5)/irisin as an essential FR-DEG in diabetic osteopathy using the Ferroptosis Database (FerrDb) and GSE189112 dataset. Initially, a diabetic mouse model was induced by intraperitoneal injection of streptozotocin (STZ), followed by intraperitoneal injection of irisin. MC3T3-E1 cells treated with high glucose (HG) were used as an in vitro model. FNDC5 overexpression plasmid was used to explore underlying mechanisms in vitro experiments. Femurs were collected for micro-CT scan, histomorphometry, and immunohistochemical analysis. Peripheral serum was collected for ELISA analysis. Cell viability was assessed using a CCK-8 kit. The levels of glutathione (GSH), malondialdehyde (MDA), iron, reactive oxygen species (ROS), and lipid ROS were detected by the corresponding kits. Mitochondria ultrastructure was observed through transmission electron microscopy (TEM). Finally, mRNA and protein expressions were examined by quantitative real‐time PCR (qRT‐PCR) and western blot analysis.ResultsThe expression of FNDC5 was found to be significantly decreased in both in vivo and in vitro models. Treatment with irisin significantly suppressed ferroptosis and improved bone loss. This was demonstrated by reduced lipid peroxidation and iron overload, increased antioxidant capability, as well as the inhibition of the ferroptosis pathway in bone tissues. Furthermore, in vitro studies demonstrated that FNDC5 overexpression significantly improved HG-induced ferroptosis and promoted osteogenesis. Mechanistic investigations revealed that FNDC5 overexpression mitigated ferroptosis in osteoblasts by inhibiting the eukaryotic initiation factor 2 alpha (eIF2α)/activated transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) pathway.ConclusionsCollectively, our study uncovered the important role of FNDC5/irisin in regulating ferroptosis of diabetic osteopathy, which might be a potential therapeutic target.