Fibronectin Type III Domain-containing Protein 5 Research Articles

The Impact of the Six Pillars of Lifestyle Medicine on Brain Health.

Dementia is growing exponentially worldwide. Unfortunately, the treatment available does not reverse any type of cognitive impairment. As a result, healthcare professionals are focusing on other evidence-based options, such as lifestyle medicine (LM). Current evidence demonstrates improvement in neurocognitive decline by applying the six pillars of LM, which includeplant-based nutrition, physical activity, stress management, avoidance of risky substances, restorative sleep, and social connections. Plant-based nutrition has a positive impact on cognition by decreasing the risk for Alzheimer's disease (AD) with high adherence to the Mediterranean-Dietary Approach to Systolic Hypertension (DASH)Intervention for Neurodegenerative Delay (MIND). Physical activity also might prevent neurocognitive decline by increasing fibronectin type III domain-containing protein 5 (FNDC5) and Irisin in the hippocampus, which increases energy expenditure and prolongs endurance. Additionally, higher perceived stress in adulthood and the use of risky substances such as alcohol, nicotine, and opioids are significantly associated with developing mild cognitive impairment and all-cause dementia. Furthermore, there is a positive correlation between poor sleep and social isolation with a rapid progression in cognitive decline. Lifestyle changes have a substantial impact on brain health. Therefore, the focus should always be on prevention as the primary treatment tool.

Brain FNDC5/Irisin Expression in Patients and Mouse Models of Major Depression.

Major depressive disorder (MDD) is a major cause of disability in adults. MDD is both a comorbidity and a risk factor for Alzheimer's disease (AD), and regular physical exercise has been associated with reduced incidence and severity of MDD and AD. Irisin is an exercise-induced myokine derived from proteolytic processing of fibronectin type III domain-containing protein 5 (FNDC5). FNDC5/irisin is reduced in the brains of AD patients and mouse models. However, whether brain FNDC5/irisin expression is altered in depression remains elusive. Here, we investigate changes in fndc5 expression in postmortem brain tissue from MDD individuals and mouse models of depression. We found decreased fndc5 expression in the MDD prefrontal cortex, both with and without psychotic traits. We further demonstrate that the induction of depressive-like behavior in male mice by lipopolysaccharide decreased fndc5 expression in the frontal cortex, but not in the hippocampus. Conversely, chronic corticosterone administration increased fndc5 expression in the frontal cortex, but not in the hippocampus. Social isolation in mice did not result in altered fndc5 expression in either frontal cortex or hippocampus. Finally, fluoxetine, but not other antidepressants, increased fndc5 gene expression in the mouse frontal cortex. Results indicate a region-specific modulation of fndc5 in depressive-like behavior and by antidepressant in mice. Our finding of decreased prefrontal cortex fndc5 expression in MDD individuals differs from results in mice, highlighting the importance of carefully interpreting observations in mice. The reduction in fndc5 mRNA suggests that decreased central FNDC5/irisin could comprise a shared pathologic mechanism between MDD and AD.

An Association Between FNDC5, PGC-1α Genetic Variants and Obesity in Chinese Children: A Case-Control Study

Fibronectin type III domain containing protein 5 (FNDC5) gene encodes irisin that regulates adipose tissue metabolism. Peroxide-proliferator-activated receptor γ coactivator 1α (PGC-1α) is a powerful promoter of mitochondrial biosynthesis and oxidative metabolism, which plays an important role in inducing heat production and energy consumption of brown fat. PGC1-α expression stimulated an increase in expression of FNDC5. The aims of this study were to analyze the association between FNDC5, PGC-1α genetic variants and overweight or obesity in Chinese children and adolescents. A total of 198 children and adolescents with overweight or obesity and 198 children and adolescents with normal weight were screened according to gender and age 1:1. The healthy eating behaviors, moderate-to-vigorous physical activity time were surveyed using food frequency questionnaire and CLASS questionnaire, respectively. Genotypes of FNDC5 and PGC-1α gene were detected using SNaPshot method. GT genotype of FNDC5 (rs16835198) increased the risk of overweight or obesity in boys (OR (95% CI): 1.68 (1.00, 2.93)) based on overdominant model; GG genotype of FNDC5 (rs16835198) decreased the risk of overweight or obesity in girls and boys (OR (95% CI): 0.45 (0.21,0.97), 0.45 (0.24, 0.83), respectively) based on dominant model; TT genotype of FNDC5 (rs16835198) increased the risk of overweight or obesity in girls based on recessive model (OR (95% CI): 2.46 (1.19, 5.05)), and based on the additive model (OR (95% CI): 3.82 (1.49, 9.80)). There was significant interaction between FNDC5 (rs16835198) and PGC-1α (rs3755863, rs8192678), healthy eating behaviors, moderate-to-vigorous physical activity time, interaction between PGC-1α (rs8192678) and moderate-to-vigorous physical activity time in the occurrence of overweight or obesity in Chinese children and adolescents. FNDC5 (rs16835198) played an independent or interactive role with PGC-1α (rs3755863, rs8192678), healthy eating behaviors, moderate-to-vigorous physical activity time in the occurrence of overweight or obesity in Chinese children and adolescents.

Does the regulation of skeletal muscle influence cognitive function? A scoping review of pre-clinical evidence.

Cognitive impairment is a major challenge for elderlies, as it can progress in a rapid manner and effective treatments are limited. Sarcopenic elderlies have a higher risk of dementia. This scoping review aims to reveal whether muscle is a mediator of cognitive function from pre-clinical evidence. PubMed, Embase, and Web of Science were searched to Feb 2nd, 2022, using the keywords (muscle) AND (cognition OR dementia OR Alzheimer) AND (mouse OR rat OR animal). The PRISMA guideline was used in this study. A total of 17 pre-clinical studies were selected from 7638 studies. 4 studies reported that muscle atrophy and injury harmed memory, functional factors, and neurons in the brain for rodents with or without Alzheimer's disease (AD). 3 studies observed exercise induced muscle to secrete factors, including lactate, fibronectin type III domain-containing protein 5 (FNDC5), and cathepsin B, which plays essential roles in the elevation of cognitive functions and brain-derived neurotrophic factor (BDNF) levels. Muscle-targeted treatments including electrical stimulation and intramuscular injections had effective remote effects on the hippocampus. 6 studies showed that muscle-specific overexpression of scFv59 and Neprilysin, or myostatin knockdown alleviated AD symptoms. 1 study showed that muscle insulin resistance also led to deficient hippocampal neurogenesis in MKR mice. The skeletal muscle is involved in the mediation of cognitive function. The evidence was established by the response in the brain (altered number of neurons, functional factors, and other AD pathological characteristics) with muscle atrophy or injury, muscle secretory factors, and muscle-targeted treatments. This study summarizes the current evidence in how muscle affects cognition in molecular levels, which supports muscle-specific treatments as potential clinical strategies to prevent cognitive dysfunction.

FNDC5 Promotes Adipogenic Differentiation of Primary Preadipocytes in Mashen Pigs.

Fibronectin type III domain-containing protein 5 (FNDC5) plays an important role in fat deposition, which can be cut to form Irisin to promote fat thermogenesis, resulting in a decrease in fat content. However, the mechanism of FNDC5 related to fat deposition in pigs is still unclear. In this research, we studied the expression of FNDC5 on different adiposes and its function in the adipogenic differentiation of primary preadipocytes in Mashen pigs. The expression pattern of FNDC5 was detected by qRT-PCR and Western blotting in Mashen pigs. FNDC5 overexpression and interference vectors were constructed and transfected into porcine primary preadipocytes by lentivirus. Then, the expression of key adipogenic genes was detected by qRT-PCR and the content of lipid droplets was detected by Oil Red O staining. The results showed that the expression of FNDC5 in abdominal fat was higher than that in back subcutaneous fat in Mashen pigs, whereas the expression in back subcutaneous fat of Mashen pigs was significantly higher than that of Large White pigs. In vitro, FNDC5 promoted the adipogenic differentiation of primary preadipocytes of Mashen pigs and upregulated the expression of genes related to adipogenesis, but did not activate the extracellular signal-regulated kinase (ERK) signaling pathway. This study can provide a theoretical basis for FNDC5 in adipogenic differentiation in pigs.

Fibronectin type III domain-containing protein 5 promotes autophagy via the AMPK/mTOR signaling pathway in hepatocellular carcinoma cells, contributing to nab-paclitaxel chemoresistance.

Chemotherapy resistance is a huge challenge in the treatment of hepatocellular carcinoma because resistance to nab-paclitaxel largely affects the efficacy of chemotherapy. An increased expression of fibronectin type III domain-containing protein 5 (FNDC5) in hepatocellular carcinoma cells can predict post-hepatectomy complications in patients with hepatocellular carcinoma and also stimulate proliferation and invasion of hepatocellular carcinoma cells; however, its role in the chemotherapy of hepatocellular carcinoma cells has never been evaluated. Thus, this study aimed to explore whether FNDC5 regulates chemoresistance in hepatocellular carcinoma. We identified by immunohistochemistry that hepatocellular carcinoma tissues had a higher FNDC5 expression than normal tissues adjacent to the cancer cells. Subsequently, knockdown of FNDC5 in hepatocellular carcinoma cells resulted in their diminished resistance to cell death after chemotherapy with nab-paclitaxel. By contrast, overexpression of FNDC5 in hepatocellular carcinoma cells increased the resistance of hepatocellular carcinoma cells to treatment. Moreover, FNDC5 mechanistically promoted autophagy via the AMPK/mTOR signaling pathway, thereby reducing cell death induced by nab-paclitaxel. Finally, we tested our hypothesis by conducting animal experiments. In conclusion, FNDC5 could be used as a biomarker for predicting chemotherapeutic efficacy in hepatocellular carcinoma treated with nab-paclitaxel chemotherapy, and as a therapeutic target to overcome resistance to nab-paclitaxel in hepatocellular carcinoma chemotherapy.

Irisin ameliorates D-galactose-induced skeletal muscle fibrosis via the PI3K/Akt pathway

Primary sarcopenia is a multicausal skeletal muscle disease associated with muscle strength and mass loss. Skeletal muscle fibrosis is one of the significant pathological manifestations associated with the development of age-related sarcopenia. Irisin, which is cleaved by the extracellular domain of fibronectin type Ⅲ domain-containing protein 5 (FNDC5), has previously been reported to exert antifibrotic effects on the heart, liver, and pancreas, but whether it can rescue skeletal muscle fibrosis remains unknown. In this study, we examined the effects of irisin on D-galactose (D-gal)-induced skeletal muscle fibroblasts. We found that D-gal-induced senescence, fibrosis, and redox imbalance were inhibited by irisin treatment. Mechanistically, irisin or FNDC5 overexpression attenuated D-gal-induced senescence, redox imbalance, and fibrosis by regulating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Overall, irisin might be a promising therapeutic candidate for age-related skeletal muscle fibrosis.

Irisin ameliorates age-associated sarcopenia and metabolic dysfunction.

Age-associated sarcopenia is characterized of progressed loss of skeletal muscle power, mass, and function, which affects human physical activity and life quality. Besides, accompanied with sarcopenia, aged population also faces a series of metabolic dysfunctions. Irisin, the cleaved form of fibronectin type III domain-containing protein 5 (FNDC5), is a myokine induced by exercise and has been shown to exert multiple beneficial effects on health. The goal of the study is to investigate the alterations of Fndc5/irisin in skeletal muscles during ageing and whether irisin administration could ameliorate age-associated sarcopenia and metabolic dysfunction. The mRNA and protein levels of FNDC5/irisin in skeletal muscle and serum from 2- and 24-month-old mice or human subjects were analysed using qRT-PCR and western blot. FNDC5/irisin knockout mice were generated to investigate the consequences of FNDC5/irisin deletion on skeletal muscle mass, as well as morphological and molecular changes in muscle during ageing via histological and molecular analysis. To identify the therapeutic effects of chronic irisin treatment in mice during ageing, in vivo intraperitoneal administration of 2mg/kg recombinant irisin was performed three times per week in ageing mice (14-month-old) for 4months or in aged mice (22-month-old) for 1month to systematically investigate irisin's effects on age-associated sarcopenia and metabolic performances, including grip strength, body weights, body composition, insulin sensitivity, energy expenditure, serum parameters and phenotypical and molecular changes in fat and liver. We showed that the expression levels of irisin, as well as its precursor Fndc5, were reduced at mRNA and protein expression levels in muscle during ageing. In addition, via phenotypic analysis of FNDC5/irisin knockout mice, we found that FNDC5/irisin deficiency in aged mice exhibited aggravated muscle atrophy including smaller grip strength (-3.23%, P<0.05), muscle weights (quadriceps femoris [QU]: -20.05%; gastrocnemius [GAS]: -17.91%; tibialis anterior [TA]: -19.51%, all P<0.05), fibre size (QU: P<0.01) and worse molecular phenotypes compared with wild-type mice. We then delivered recombinant irisin protein intraperitoneally into ageing or aged mice and found that it could improve sarcopenia with grip strength (+18.42%, P<0.01 or +13.88%, P<0.01), muscle weights (QU: +9.02%, P<0.01 or +16.39%, P<0.05), fibre size (QU: both P<0.05) and molecular phenotypes and alleviated age-associated fat tissues expansion, insulin resistance and hepatic steatosis (all P<0.05), accompanied with altered gene signatures. Together, this study revealed the importance of irisin in the maintenance of muscle physiology and systematic energy homeostasis during ageing and suggested a potent therapeutic strategy against age-associated metabolic diseases via irisin administration.

High-fat diet and palmitate inhibits FNDC5 expression via AMPK-Zfp57 pathway in mouse muscle cells

Irisin, a muscle-secreted cytokine involved in maintaining glucose homeostasis and improving insulin resistance, is generated from the precursor fibronectin type Ⅲ domain-containing protein 5 (FNDC5) by specific proteases. Zinc-finger protein Zfp57, a transcription factor that maintains the methylation during early embryonic development, is also reported to be associated with diabetes mellitus. However, the association between Zfp57 and FNDC5 is still unclear. In our study, we explored the detailed regulatory effect of Zfp57 on FNDC5 expression. In this study, we found that high-fat diet or saturated fatty acid palmitate increased the Zfp57 expression and decreased FNDC5 expression in muscle tissue or C2C12 myotubes. RNA sequencing analysis disclosed effects of the high-fat diet on genes associated with insulin resistance and the AMP-activated protein kinase (AMPK) signaling pathway in muscle tissue of mice. Chromatin immunoprecipitation experiments revealed that Zfp57 binds the FNDC5 gene promoter at positions −308 to −188. Moreover, Zfp57 overexpression inhibited FNDC5 expression, and Zfp57 knockdown alleviated the inhibitory effect of palmitate on FNDC5 expression in C2C12 myotubes. In addition, in vivo and in vitro studies demonstrated that activation of the AMPK pathway by 5-Aminoimidazole-4-carboxamide riboside (AICAR) or metformin mitigated the inhibitory effect of Zfp57 on FNDC5 expression and improved insulin resistance. These findings collectively suggest that high-fat diet and palmitate inhibit the AMPK pathway to increase Zfp57 expression, which in turn induces FNDC5 inhibition, to further aggravate insulin resistance.

Expression analysis of irisin during different development stages of skeletal muscle in mice

BackgroundAs a newly discovered muscle factor secreted by skeletal muscle cells, irisin is a polypeptide fragment formed from hydrolysis of fibronectin type Ⅲ domain-containing protein 5 (FNDC5). Irisin can promote beigeing of white adipose tissue (WAT) and regulate glucose and lipid metabolisms. However, the functions of irisin in skeletal muscle development remain largely unknown. In order to characterize the expression of irisin, this study investigated the expression of irisin precursor FNDC5 in myoblasts and skeletal muscles during different developmental stages of SPF mice. ResultsThe Western blot, quantitative real-time PCR (qRT-PCR), and immunofluorescence assay results showed that FNDC5 was expressed in all the developmental stages of myoblasts and gastrocnemius, but its expression differed at different stages. FNDC5 protein exhibited the highest expression in gastrocnemius of sexually mature mice, followed by elderly mice and adolescent mice, and it displayed the lowest expression in pups. Additionally, FNDC5 protein was mainly expressed in cytoplasm, and it had the highest expression in primary myoblasts, followed by the myotubes with the lowest expression in C2C12 myogenic cells. ConclusionsOverall, FNDC5 was mainly expressed in cytoplasm and extracellular matrix with different expression levels at different developmental stages of skeletal muscle cells and tissues in mice. This study will provide new strategies for promoting skeletal muscle development and treating muscle- and metabolism-related disease by using irisin.

Irisin stimulates protective signaling pathways in rat hippocampal neurons.

Physical exercise stimulates neuroprotective pathways, has pro-cognitive actions, and alleviates memory impairment in Alzheimer’s disease (AD). Irisin is an exercise-linked hormone produced by cleavage of fibronectin type III domain containing protein 5 (FNDC5) in skeletal muscle, brain and other tissues. Irisin was recently shown to mediate the brain benefits of exercise in AD mouse models. Here, we sought to obtain insight into the neuroprotective actions of irisin. We demonstrate that adenoviral-mediated expression of irisin promotes extracellular brain derived neurotrophic factor (BDNF) accumulation in hippocampal cultures. We further show that irisin stimulates transient activation of extracellular signal-regulated kinase 1/2 (ERK 1/2), and prevents amyloid-β oligomer-induced oxidative stress in primary hippocampal neurons. Finally, analysis of RNA sequencing (RNAseq) datasets shows a trend of reduction of hippocampal FNDC5 mRNA with aging and tau pathology in humans. Results indicate that irisin activates protective pathways in hippocampal neurons and further support the notion that stimulation of irisin signaling in the brain may be beneficial in AD.

Whole Body Vibration Improves Brain and Musculoskeletal Health by Modulating the Expression of Tissue-Specific Markers: FNDC5 as a Key Regulator of Vibration Adaptations.

Whole body vibration (WBV) is well known to exert beneficial effects on multiple tissues, improving synaptic transmission, muscle mass, bone quality, and reducing anxiety and depressive behavior. However, the underlying molecular mechanisms are not yet fully understood, and organs and tissues may respond differently to the vibratory stimulus depending on multiple factors. Therefore, we investigated the WBV effects on the brain and musculoskeletal tissue of 4-month-old young mice, evaluating synaptic plasticity by electrophysiological recordings and tissue organization by histology and histomorphometric analysis. Specifically, WBV protocols were characterized by the same vibration frequency (45 Hz), but different in vibration exposure time (five series of 3 min for the B protocol and three series of 2 min and 30 s for the C protocol) and recovery time between two vibration sessions (1 min for the B protocol and 2 min and 30 s for the C protocol). In addition, immunohistochemistry was conducted to evaluate the expression of fibronectin type III domain-containing protein 5 (FNDC5), as well as that of tissue-specific markers, such as brain-derived neurotrophic factor (BDNF) in brain, myostatin in muscle and collagen I (COL-1) in bone. Our results suggest that the WBV effects depend closely on the type of protocol used and support the hypothesis that different organs or tissues have different susceptibility to vibration. Further studies will be needed to deepen our knowledge of physiological adaptations to vibration and develop customized WBV protocols to improve and preserve cognitive and motor functions.

Implication of Irisin in Different Types of Cancer: A Systematic Review and Meta-Analysis.

Cancer is a set of diseases characterized by several hallmark properties, such as increased angiogenesis, proliferation, invasion, and metastasis. The increased angiogenic activity constantly supplies the tumors with nutrients and a plethora of cytokines to ensure cell survival. Along these cytokines is a newly discovered protein, called irisin, which is released into the circulation after physical exercise. Irisin is the product of fibronectin type III domain-containing protein 5 (FNDC5) proteolytic cleavage. Recently it has been the topic of investigation in several types of cancer. In this study, we conducted a systematic review and meta-analysis to investigate its implication in different types of cancer. Our results suggest that irisin expression is decreased in cancer patients, thus it can be used as a valid biomarker for the diagnosis of several types of cancer. In addition, our results indicate that irisin may have an important role in tumor progression and metastasis since it is involved in multiple signaling pathways that promote cell proliferation and migration.

The emerging neuroprotective roles of exerkines in Alzheimer's disease.

Despite the extensive knowledge of the beneficial effects of physical exercise, a sedentary lifestyle is still a predominant harm in our society. Sedentarism is one of the major modifiable risk factors for metabolic diseases such as diabetes mellitus, obesity and neurological disorders, including Alzheimer’s disease (AD)–characterized by synaptic failure, amyloid protein deposition and memory loss. Physical exercise promotes neuroprotective effects through molecules released in circulation and mediates the physiological crosstalk between the periphery and the brain. This literature review summarizes the current understanding of the roles of exerkines, molecules released during physical exercise, as systemic and central factors that mediate the beneficial effects of physical exercise on cognition. We highlight the neuroprotective role of irisin—a myokine released from the proteolytic cleavage of fibronectin type III domain-containing protein 5 (FNDC5) transmembrane protein. Lastly, we review evidence pointing to physical exercise as a potential preventative and interventional strategy against cognitive decline in AD.

Exerkine fibronectin type-III domain-containing protein 5/irisin-enriched extracellular vesicles delay vascular ageing by increasing SIRT6 stability.

Exercise confers protection against cardiovascular ageing, but the mechanisms remain largely unknown. This study sought to investigate the role of fibronectin type-III domain-containing protein 5 (FNDC5)/irisin, an exercise-associated hormone, in vascular ageing. Moreover, the existence of FNDC5/irisin in circulating extracellular vesicles (EVs) and their biological functions was explored. FNDC5/irisin was reduced in natural ageing, senescence, and angiotensin II (Ang II)-treated conditions. The deletion of FNDC5 shortened lifespan in mice. Additionally, FNDC5 deficiency aggravated vascular stiffness, senescence, oxidative stress, inflammation, and endothelial dysfunction in 24-month-old naturally aged and Ang II-treated mice. Conversely, treatment of recombinant irisin alleviated Ang II-induced vascular stiffness and senescence in mice and vascular smooth muscle cells. FNDC5 was triggered by exercise, while FNDC5 knockout abrogated exercise-induced protection against Ang II-induced vascular stiffness and senescence. Intriguingly, FNDC5 was detected in human and mouse blood-derived EVs, and exercise-induced FNDC5/irisin-enriched EVs showed potent anti-stiffness and anti-senescence effects in vivo and in vitro. Adeno-associated virus-mediated rescue of FNDC5 specifically in muscle but not liver in FNDC5 knockout mice, promoted the release of FNDC5/irisin-enriched EVs into circulation in response to exercise, which ameliorated vascular stiffness, senescence, and inflammation. Mechanistically, irisin activated DnaJb3/Hsp40 chaperone system to stabilize SIRT6 protein in an Hsp70-dependent manner. Finally, plasma irisin concentrations were positively associated with exercise time but negatively associated with arterial stiffness in a proof-of-concept human study. FNDC5/irisin-enriched EVs contribute to exercise-induced protection against vascular ageing. These findings indicate that the exerkine FNDC5/irisin may be a potential target for ageing-related vascular comorbidities.

Irisin attenuates sepsis-induced cardiac dysfunction by attenuating inflammation-induced pyroptosis through a mitochondrial ubiquitin ligase-dependent mechanism.

Sepsis-induced cardiac dysfunction is a leading cause of mortality in intensive care units. However, the molecular mechanisms underlying septic cardiomyopathy remain elusive. Irisin is a cleaved product of fibronectin type III domain-containing protein 5 (FNDC5) that protects the heart from ischemia/reperfusion injury through upregulation of mitochondrial ubiquitin ligase (MITOL). Gasdermin D (GSDMD)-dependent pyroptosis plays a pivotal role in septic cardiomyopathy by regulating mitochondrial homeostasis. However, whether irisin can regulate MITOL to inhibit GSDMD-dependent pyroptosis in septic cardiomyopathy is yet to be investigated. Thus, this study was designed to explore the role of irisin in septic cardiomyopathy and its underlying molecular mechanisms. Our results demonstrate that irisin improves cardiac function against sepsis-induced cardiac dysfunction by reducing cardiac inflammation and myocardial pyroptosis. Using MITOL siRNA in vitro, the results revealed that the protective role of irisin against lipopolysaccharide (LPS)-induced cell injury was mediated by MITOL activation and the resulting inhibition of GSDMD-dependent pyroptosis. Moreover, irisin alleviated LPS-induced H9c2 cell injury by suppressing IL-1β expression and reducing serum LDH and CK-MB concentrations in a MITOL/GSDMD-dependent manner. Collectively, our data suggest that irisin treatment ameliorates cardiac dysfunction in septic cardiomyopathy by activating MITOL and inhibiting GSDMD-dependent pyroptosis. These findings highlight the clinical relevance and therapeutic potential of irisin and MITOL for the management of sepsis-induced cardiac dysfunction.

Irisin/FNDC5 influences myogenic markers on skeletal muscle following high and moderate-intensity exercise training in STZ-diabetic rats.

In the present study, we investigated the effects of high-intensity interval training (HIIT) versus moderate-intensity continuous training (MICT) on irisin and expression of myogenic markers (paired box 7 (Pax7), myogenic differentiation 1 (MyoD), myogenin) in skeletal muscle of diabetic rats. Eighty-four male Wistar rats (6weeks of age) were randomly divided into seven groups (n = 12): basic control (Co Basic), 8weeks control (Co 8w), diabetes mellitus (DM), HIIT, DM + HIIT, MICT, and DM + MICT groups. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ). The protocol was characterized by running on a rodent treadmill with moderate intensity (60-70% ), 60min per session, 5days/week, for 6weeks. HIIT consisted of six 3-min runs at a high intensity (80-90% ) alternated with 2-min running at low intensity (50% ), 30min per session, 5days/week, for 6weeks. Results showed that DM decreased myoblast markers compared to Co Basic and Co 8w groups. Fibronectin type III domain-containing protein 5 (FNDC5) mRNA decrease was correlated with myoblast markers (Pax7 r = 0.632, p = 0.027; MyoD r = 0.999, p = 0.001; myogenin r = 1.000, p = 0.001) in DM group. DM + MICT significantly increased gene expression of MyoD, myogenin, and FNDC5 compared to DM and DM + HIIT. The results also showed that the intensity and duration of exercise on the treadmill were effective in stimulating irisin and myogenic markers after DM.

Reduced irisin levels in patients with acromegaly.

Several metabolic disturbances are seen in acromegaly however, data regarding the contribution of irisin to these disturbances is currently insufficient. In a cohort of patients with acromegaly, we measured serum irisin levels in active and controlled cases and determined independent factors that effect serum irisin including fibronectin type III domain-containing protein 5 (FNDC5) genotyping. A cross-sectional case-control study including 46 patients with acromegaly (28F/18M, age: 50.3±12.1year, BMI: 30.7±5.1kg/m2) and 81 age-, gender-, body mass index- and body composition-matched healthy controls was conducted. 15 acromegalic patients (33%) had active disease. Irisin levels were measured by enzyme-linked immunosorbent assay. Three different regions (rs3480, rs1746661, and rs16835198) of FNDC5 were subjected to polymorphism analyses. Both groups were overweight and had similar body composition. Irisin levels were lower in patients with acromegaly than controls (median [IQR]: 44.8 [41.7-46.7] ng/mL vs. 51.7 [45.5-60.1] ng/mL, p≤0.001, respectively). Active and controlled patients had similar irisin levels. Irisin was not correlated with growth hormone (GH), insulin-like growth factor 1 (IGF-1), and IGF-1 index. In multiple linear regression model, somatostatin receptor ligand use (β=-20.30, 95% CI [-34]-[-6], p=0.006) was determined as the only independent factor that affect serum irisin. Serum irisin levels are low in patients with acromegaly who are on somatostatin receptor ligand therapy. Single nucleotide polymorphisms (SNPs) of FNDC5 have no independent effects on circulating irisin levels under somatostatin ligand action. Endocrine muscle functions also seem to be regulated by somatostatin action, which requires further studies.

Exercise-induced FNDC5/irisin protects nucleus pulposus cells against senescence and apoptosis by activating autophagy

Intervertebral disc degeneration (IVDD) is a major cause of low back pain (LBP), and excessive senescence and apoptosis of nucleus pulposus (NP) cells are major pathological changes in IVDD. Physical exercise could effectively delay the process of intervertebral disc degeneration; however, its mechanism is still largely unknown. Irisin is an exercise-induced myokine released upon cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), and its levels increase after physical exercise. Here, we show that after physical exercise, FNDC5/irisin levels increase in the circulation and NP, senescence and apoptosis are reduced, autophagy is activated in NP tissue, and the progression of IVDD is delayed. Conversely, after knocking out FNDC5, the benefits of physical exercise are compromised. Moreover, the overexpression of FNDC5 in NP tissue effectively alleviated the degeneration of the intervertebral disc (IVD) in rats. By showing that FNDC5/irisin is an important mediator of the beneficial effects of physical exercise in the IVDD model, the study proposes FNDC5/irisin as a novel agent capable of activating autophagy and protecting NP from senescence and apoptosis.

Irisin Attenuates Muscle Impairment during Bed Rest through Muscle-Adipose Tissue Crosstalk.

Simple SummaryIrisin is a known myokine secreted mainly by the muscle that is produced after physical activity. It induces browning in the adipose tissue with a consequent increase in mitochondrial oxidation of lipids and reduction of insulin resistance; thus, it has been hypothesized that irisin was the molecule mediating most of the beneficial effects related to exercise on adipose tissue and consequently on the whole organism. In our study we observed that extreme physical inactivity induces the loss of muscle mass and function, and an increase in the body adipose tissue as expected. However, of note, circulating irisin levels were increased secondary to enhanced irisin synthesis mainly from adipose tissue rather than muscle. In addition, subjects who produced more irisin had reduced muscle impairment. Therefore, our hypothesis is that there is negative feedback within the muscle-adipose tissue crosstalk, specifically not only does the muscle influence the adipose tissue through irisin during exercise, but also the adipose tissue protects the muscle during inactivity.The detrimental effect of physical inactivity on muscle characteristics are well known. Irisin, an exercise-induced myokine cleaved from membrane protein fibronectin type III domain-containing protein-5 (FNDC5), mediates at least partially the metabolic benefits of exercise. This study aimed to assess the interplay between prolonged inactivity, circulating irisin, muscle performance, muscle fibers characteristics, as well as the FNDC5 gene expression (FNDC5ge) in muscle and adipose tissue among healthy subjects. Twenty-three healthy volunteers were tested before and after 14 days of Bed Rest, (BR). Post-BR circulating levels of irisin significantly increased, whereas body composition, muscle performance, and muscle fiber characteristics deteriorated. Among the subjects achieving the highest post-BR increase of irisin, the lowest reduction in maximal voluntary contraction and specific force of Fiber Slow/1, the highest increase of FNDC5ge in adipose tissue, and no variation of FNDC5ge in skeletal muscle were recorded. Subjects who had the highest FNDC5ge in adipose tissue but not in muscle tissue showed the highest circulating irisin levels and could better withstand the harmful effect of BR.