Myokine Irisin Research Articles

Determination of irisin and nitric oxide levels in patients with metabolic impairments in intensive care unit

Objective: The newly discovered myokine irisin has been proposed to affect physical activity. However, clinical and functional studies on the association of irisin with muscle mass, and metabolic status remain controversial. The nitric oxide is a molecule produced by the endothelium and in a variety of additional cells, including skeletal muscle. The aim of the study was to determine irisin and nitric oxide (NO) levels in physically inactive patients with severe acute metabolic disorders in intensive care unit. Material and Method: Total of 80 subjects were divided into 3 groups: healthy control (n=20), cerebrovascular disease (including hemi and paraplegic patients) (n=40), pulmonary disease (PD) (n=20). Plasma irisin levels were analyzed using a commercial ELISA kits. The total serum nitrate and nitrite was measured using a Nitrate/Nitrite Colorimetric Assay Kit. Results: We have found significantly higher irisin levels (322.8±20.4 ng/ml) in patients with cerebrovascular disease (p=0.0001) and (302.6±40.2 ng/ml) in patients with PD (p=0.01) compared to (171.4±10.5 ng/ml) control subjects. In addition, higher NO levels were observed (42.42±1.9 μM) in patients with cerebrovascular disease (p<0.001) and (44.36±2.7 μM) in patients with PD (p<0.001), compared to (27.65±0.7 μM) control subjects. Discussion: Observation of higher levels of irisin and NO in critically ill intensive care unit patients may indicate the protective roles of these agents against serious metabolic impairments.

Current Evidence of the Role of the Myokine Irisin in Cancer.

Simple SummaryRegular exercise/physical activity is beneficial for the health of an individual and lowers the risk of getting different diseases, including cancer. How exactly exercise results in these health benefits is not known. Recent studies suggest that the molecule irisin released by muscles into the blood stream after exercise may be responsible for these effects. This review summarizes all the available in vitro/cell culture, animal and human studies that have investigated the relationship between cancer and irisin with the aim to shed light and understand the possible role of irisin in cancer. The majority of the in vitro studies indicate anticancer properties of irisin, but more animal and human studies are required to better understand the exact role of irisin in cancer.Cancer is a disease associated with extreme human suffering, a huge economic cost to health systems, and is the second leading cause of death worldwide. Regular physical activity is associated with many health benefits, including reduced cancer risk. In the past two decades, exercising/contracting skeletal muscles have been found to secrete a wide range of biologically active proteins, named myokines. Myokines are delivered, via the circulation, to different cells/tissues, bind to their specific receptors and initiate signaling cascades mediating the health benefits of exercise. The present review summarizes the existing evidence of the role of the myokine irisin in cancer. In vitro studies have shown that the treatment of various cancer cells with irisin resulted in the inhibition of cell proliferation, survival, migration/ invasion and induced apoptosis by affecting key proliferative and antiapoptotic signaling pathways. However, the effects of irisin in humans remains unclear. Although the majority of the existing studies have found reduced serum irisin levels in cancer patients, a few studies have shown the opposite. Similarly, the majority of studies have found increased levels of irisin in cancer tissues, with a few studies showing the opposite trend. Clearly, further investigations are required to determine the exact role of irisin in cancer.

Irisin Precursor FNDC5 and Glycemic Control in Patients With Type 2 Diabetes

Introduction: Irisin is a newly discovered myokine whose expression is induced by exercise and PGC1α. Studies have reported its action on adipose tissue cells, leading to their “browning,” and consequent increase in energy expenditure and thermogenesis. In the first description of this hormone, which is a product of cleavage of its precursor (protein 5 containing fibronectin type III domain), elevated irisin levels were associated with improved insulin sensitivity, weight reduction, and better glucose tolerance in animal models. Hence, studies have tried to characterize the role of irisin in glucose regulation, with controversial results. Muscle mass has been a good predictor of irisin circulation in humans and, because it is predominantly synthesized and secreted by skeletal muscle, its use as a potential biomarker of sarcopenia has been investigated. Methods: The aim of this study was to evaluate serum FNDC5 levels according to clinical and metabolic parameters as well as muscle mass from patients with type 2 diabetes (T2DM). Body composition was evaluated by Dual X-ray absortptiometry (DXA) and multifrequency Bioelectric Impedance (BIA) and FNDC5 was measured using an ELISA kit. Results: We evaluated 44 women with type-2 diabetes, mean age of 61.95±8.52 years, mean diabetes duration of 10.25±7.06 years, mean HbA1c of 7.66±1.37, mean fasting plasma glucose of 149.11±38.26 mg/dL, mean BMI of 29.20±5.15 kg/m2, and mean abdominal circumference of 95.02±12.80 cm. Mean FNDC5/irisin was 18.69±3.67 ng/mL. Although there were no differences in DXA and BIA analyses according to first and top quartiles of serum FNDC5, we identified a negative correlation of serum FNDC5 with fasting plasma glucose (−0.479; P=0.001) and a positive correlation with age (0.422; P=0.004). Conclusion: our data demonstrated that increased serum FNDC5 is related to increased age and poor glycemic control in T2DM. Reference: (1) Perakakis N et al., Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol. 2017 (2) Hyun HP et al., The novel myokine irisin:clinical implications and potential role as a biomarker for sarcopenia in postmenopausal women. Endocrine. 2018.

Multiple Roles in Neuroprotection for the Exercise Derived Myokine Irisin.

Exercise has multiple beneficial effects on health including decreasing the risk of neurodegenerative diseases. Such effects are thought to be mediated (at least in part) by myokines, a collection of cytokines and other small proteins released from skeletal muscles. As an endocrine organ, skeletal muscle synthesizes and secretes a wide range of myokines which contribute to different functions in different organs, including the brain. One such myokine is the recently discovered protein Irisin, which is secreted into circulation from skeletal muscle during exercise from its membrane bound precursor Fibronectin type III domain-containing protein 5 (FNDC5). Irisin contributes to metabolic processes such as glucose homeostasis and browning of white adipose tissue. Irisin also crosses the blood brain barrier and initiates a neuroprotective genetic program in the hippocampus that culminates with increased expression of brain derived neurotrophic factor (BDNF). Furthermore, exercise and FNDC5/Irisin have been shown to have several neuroprotective effects against injuries in ischemia and neurodegenerative disease models, including Alzheimer’s disease. In addition, Irisin has anxiolytic and antidepressant effects. In this review we present and summarize recent findings on the multiple effects of Irisin on neural function, including signaling pathways and mechanisms involved. We also discuss how exercise can positively influence brain function and mental health via the “skeletal muscle-brain axis.” While there are still many unanswered questions, we put forward the idea that Irisin is a potentially essential mediator of the skeletal muscle-brain crosstalk.

The Myokine Irisin Promotes Osteogenic Differentiation of Dental Bud-Derived MSCs.

Simple SummaryIrisin is a recently discovered protein, mainly produced in the muscle tissue, whose action is proving effective in many other tissues. The crosstalk between muscle and bone has been long since demonstrated, and physical activity has shown to have an impressive positive effect in both tissues. Irisin production increases with exercising and drops with sedentariness and aging, indicating that the molecule is involved in sarcopenia and in bone mass reduction. Although skeleton is target of irisin, its mechanism of action on bone cells has not yet been completely elucidated. The aim of this work is to analyze the effect of irisin on osteoblast differentiation; to this purpose, we used a stem cell model reproducing the osteoblastogenesis and the bone-forming processes. We performed an in vitro study exploring the main osteoblast markers in the presence of irisin. We found that irisin has an impressive effect on the most peculiar osteoblast feature: the bone mineral matrix secretion process. Moreover, irisin demonstrated an inductive effect on osteoblast osteocalcin production. Both results suggest a stimulating effect of irisin in bone formation. The association we observed between irisin addition and osteoblast osteocalcin production should be further investigated.The myokine irisin, well known for its anabolic effect on bone tissue, has been demonstrated to positively act on osteoblastic differentiation processes in vitro. Mesenchymal stem cells (MSCs) have captured great attention in precision medicine and translational research for several decades due to their differentiation capacity, potent immunomodulatory properties, and their ability to be easily cultured and manipulated. Dental bud stem cells (DBSCs) are MSCs, isolated from dental tissues, that can effectively undergo osteoblastic differentiation. In this study, we analyzed, for the first time, the effects of irisin on DBSC osteogenic differentiation in vitro. Our results indicated that DBSCs were responsive to irisin, showed an enhanced expression of osteocalcin (OCN), a late marker of osteoblast differentiation, and displayed a greater mineral matrix deposition. These findings lead to deepening the mechanism of action of this promising molecule, as part of osteoblastogenesis process. Considering the in vivo studies of the effects of irisin on skeleton, irisin could improve bone tissue metabolism in MSC regenerative procedures.

NLRP3-mediated pyroptosis aggravates pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction in mice: cardioprotective role of irisin

The exact mechanism of myocardial hypertrophy has not been completely elucidated. NOD-like receptor protein 3 (NLRP3) and the pyroptotic cascade play a critical role in cardiac hypertrophy and inflammation. The myokine irisin can inhibit NLRP3 activation, although its exact mechanism of action is unknown. In this study, we induced cardiac hypertrophy in a mouse model via aortic constriction (TAC) to further explore the pathological role of NLRP3 inflammasome-mediated pyroptosis and the potential therapeutic effects of irisin. Cardiac hypertrophy significantly increased the percentage of apoptotic cells and upregulated IL-1β, cleaved caspase-1, and GSDMD-N that lie downstream of the NLRP3 inflammasome. Subsequently, irisin was co-administered to the TAC mice or angiotensin II (Ang-II)-treated cardiomyocytes to observe whether it could attenuate pyroptosis and cardiac hypertrophy. We established a direct association between pyroptosis and cardiac hypertrophy and found that pharmacological or genetic inhibition of NLRP3 attenuated cardiac hypertrophy. Furthermore, ectopic overexpression of NLRP3 abrogated the cardioprotective effects of irisin. To summarize, pyroptosis is a pathological factor in cardiac hypertrophy, and irisin is a promising therapeutic agent that inhibits NLRP3-mediated pyroptosis of cardiomyocytes.

Intestinal Alkaline Phosphatase Combined with Voluntary Physical Activity Alleviates Experimental Colitis in Obese Mice. Involvement of Oxidative Stress, Myokines, Adipokines and Proinflammatory Biomarkers

Intestinal alkaline phosphatase (IAP) is an essential mucosal defense factor involved in the process of maintenance of gut homeostasis. We determined the effect of moderate exercise (voluntary wheel running) with or without treatment with IAP on the course of experimental murine 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis by assessing disease activity index (DAI), colonic blood flow (CBF), plasma myokine irisin levels and the colonic and adipose tissue expression of proinflammatory cytokines, markers of oxidative stress (SOD2, GPx) and adipokines in mice fed a standard diet (SD) or high-fat diet (HFD). Macroscopic and microscopic colitis in sedentary SD mice was accompanied by a significant decrease in CBF, and a significant increase in the colonic expression of tumor necrosis factor-alpha (TNF-α), IL-6, IL-1β and leptin mRNAs and decrease in the mRNA expression of adiponectin. These effects were aggravated in sedentary HFD mice but reduced in exercising animals, potentiated by concomitant treatment with IAP, especially in obese mice. Exercising HFD mice demonstrated a substantial increase in the mRNA for adiponectin and a decrease in mRNA leptin expression in intestinal mucosa and mesenteric fat as compared to sedentary animals. The expression of SOD2 and GPx mRNAs was significantly decreased in adipose tissue in HFD mice, but these effects were reversed in exercising mice with IAP administration. Our study shows for the first time that the combination of voluntary exercise and oral IAP treatment synergistically favored healing of intestinal inflammation, strengthened the antioxidant defense and ameliorated the course of experimental colitis; thus, IAP may represent a novel adjuvant therapy to alleviate inflammatory bowel disease (IBD) in humans.

The effect of Irisin on bone cells in vivo and in vitro.

The myokine Irisin, produced during physical exercise, has an anabolic effect on bone, both in vitro and in vivo. Very recently, using a controlled in vitro 3D cell model to mimic the bone microenvironment aboard the International Space Station, it has been shown that Irisin treatment in microgravity prevents the down-regulation of the transcription factors Atf4, Runx2 and Osterix, as well as Collagen I and Osteoprotegerin proteins, crucial for osteoblast differentiation in physiologic conditions. Irisin action has also been investigated in human subjects, in which it correlates with bone health status, supporting its physiological importance also in human bone, both in healthy subjects and in patients suffering from diseases related to bone metabolism, such as hyperparathyroidism and type 1 diabetes. Low levels of circulating Irisin have been found in post-menopausal women affected by hyperparathyroidism. Furthermore, Irisin is positively correlated with bone strength in athletes and bone mineral density in football players. Moreover, in healthy children, Irisin is positively associated with bone mineral status and in children with type 1 diabetes, Irisin is positively correlated with improved glycemic control and skeletal health. In this review, we will focus on recent findings about Irisin action on microgravity induced bone loss and on osteocyte activity and survival through its αV/β5 integrin receptor.

Association of Circulating Irisin Levels with Adiposity and Glucose Metabolic Profiles in a Middle-Aged Chinese Population: A Cross-Sectional Study.

ObjectiveThe myokine irisin has been proposed to affect obesity and metabolism disorders. However, data about the association of irisin with obesity and glucose metabolic status in humans remains controversial, and limited data are available concerning the Chinese population. This study aimed to evaluate the association between serum irisin concentrations and obesity, as well as glucose metabolic and cardiovascular factors in the middle-aged physical activity-matched Chinese Han race population.MethodsA total of 740 participants were included in this cross-sectional study, who were divided into a normal weight (NW) group, overweight/obese (OB) group, normal weight type 2 diabetes (DM-NW) group and overweight/obese diabetes (DM-OB) group, and physical activity was evaluated and matched for the four groups. Circulating irisin levels were analyzed and compared among the groups with different adiposity and glucose status. Linear regression analysis was performed to test the relationship between serum irisin and adiposity indices, glucose metabolic and other cardiovascular risk factors.ResultsCirculating irisin levels were significantly correlated with higher levels of direct and indirect adiposity markers, including BMI, waist circumference and fat mass, and other cardiovascular risk factors, such as plasma triglyceride and low-density lipoprotein cholesterol level (p < 0.01). Diabetes patients had lower irisin levels compared to non-diabetes participants, in either normal weight and obese group, resulting in a correlation of irisin with HbA1c, HOMA-IR and HOMA-IS (p < 0.01). Linear regression analysis demonstrated that irisin serum concentrations were independently associated with sex, BMI, HbA1c, HOMA-IR and HOMA-IS (R2 = 0.465).ConclusionThese data indicated that circulating irisin was affected by adiposity and glucose metabolism condition in the middle-aged Chinese population. The increase of irisin under conditions of obesity may indicate its physiological function to improve glucose tolerance which is often impaired in obese subjects, but this compensatory secretion of irisin seems likely to be progressing to a secretion failure once diabetes developed.

The myokine irisin: localization and effects in swine late medium and large antral ovarian follicle

Irisin is mainly synthesized by skeletal muscle tissue, where it is believed to be responsible for the benefits of exercise on metabolism and cardiovascular system. In adipose tissue, its best-known effect is the browning of white adipocytes, resulting in the increase of thermogenesis and energy expenditure. As it has been largely documented that metabolic dysfunctions can frequently be associated with reductions in fertility, the possible involvement of this molecule in the regulation of reproductive processes represents an issue to be addressed. On this basis, the first aim of this work was the evaluation of the presence of irisin in the swine ovary; then, we investigated the expression of the associated molecules FNDC5, PGC-1α, and PPAR-γ. To verify a potential modulatory role both on ovarian function and on redox status, cell growth, steroidogenesis, production of superoxide anion and nitric oxide, the nonenzymatic antioxidant scavengers, were assessed in vitro on granulosa cells treated with increasing concentrations of irisin (50, 100, and 150 ng/mL). The data collected demonstrate the presence of irisin in swine ovarian follicle. Moreover, the highest concentrations tested stimulated metabolic activity and inhibited cell proliferation (P < 0.05); the peptide exerted a biphasic effect on progesterone (P < 0.01) production and, at the highest concentrations, inhibited nitric oxide while stimulated the nonenzymatic antioxidant power (P < 0.05). Superoxide anion and estradiol 17β were unaffected. The demonstration of the local presence of irisin at the ovarian level and the highlighted effects allow us to qualify this molecule as a potential physiological regulator of follicular function.

2094-P: Effects of Irisin on Human Pancreatic Islets from Type 2 Diabetic Subjects

Irisin is a hormone secreted by skeletal muscle following physical activity and excess of saturated fatty acids, able to improve metabolic homeostasis and promote energy expenditure. In a previous study, we have demonstrated that, in beta-cells, irisin promotes proliferation and glucose-stimulated insulin secretion (GSIS), increases insulin content levels, and reduces lipotoxicity-induced apoptosis. The aim of this study was to evaluate the effects of irisin on the function and survival of pancreatic islets isolated from patients with type 2 diabetes mellitus (T2DM), characterized by reduced ability to secrete insulin and high levels of apoptosis, and to investigate the molecular mechanisms underlying this action. Pancreatic islets isolated from T2DM patients (n=7) and nondiabetic subjects (ND) (n=3), as well as INS-1E cells, were exposed to 100 nM irisin for different times. GSIS, insulin content, apoptosis and cytoplasmic calcium levels were measured by ELISA assays; the activation of the main mediators of beta-cell intracellular signalling (AKT, CREB and PKA) was evaluated by immunoblotting. Irisin increased GSIS approximately 2-fold (p&amp;lt;0.05) in both ND and T2DM islets. Notably, in T2DM islets, characterized by reduced GSIS, this was restored to the levels of ND islets. In addition, irisin increased insulin content (1.6-fold in ND, 1.9-fold in T2DM, p&amp;lt;0.05) and tendentially decreased apoptosis levels only in T2DM islets. Moreover, irisin was able to activate AKT and CREB under conditions of high glucose in the ND islets, without changing cytoplasmic calcium levels. In contrast, in the T2DM islets, irisin did not induce AKT or CREB activation. In conclusion, the myokine irisin is able to increase the secretory function and survival of human pancreatic islets and to improve the functional defects typical of the T2DM islets. The mechanisms underlying the secretagogue effects of irisin in the T2DM islets do not apparently involve the known signaling machinery of this novel hormone. Disclosure N. Marrano: None. A. Natalicchio: Consultant; Self; AstraZeneca, Novo Nordisk Inc., Sanofi-Aventis. G. Biondi: None. A. Cignarelli: None. L. Vincenti: None. L.G. Lupo: None. S. Perrini: None. L. Laviola: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi-Aventis. Speaker’s Bureau; Self; Abbott, Medtronic. F. Giorgino: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., LifeScan, Inc., MedImmune, Merck Sharp &amp; Dohme Corp., Roche Diabetes Care, Sanofi. Research Support; Self; Eli Lilly and Company, LifeScan, Inc., Takeda Development Centre Europe Ltd. Funding European Union (AIM1810057)

Hippocampal injection of the exercise-induced myokine irisin suppresses acute stress-induced neurobehavioral impairment in a sex-dependent manner.

Stress disrupts a variety of neural processes, including reducing levels of brain-derived neurotrophic factor (BDNF) in the hippocampus. In contrast, exercise increases BDNF and is beneficial for health and cognition. Irisin is a myokine that is released into circulation during exercise. Although its main known functions are browning white adipose tissue and improving glucose homeostasis, Irisin also mediates the activation of an exercise-induced BDNF-mediated neuroprotective pathway in the hippocampus. Therefore, we tested the hypothesis that Irisin can counteract the deleterious effects of acute stress when directly injected into the hippocampus. To test our hypothesis, we used a 3-hr long physical restraint stress event in adult female and male mice. Acute stress resulted in sex-dependent increased anxiety-like behaviors and memory impairment in a combined open field/novel object recognition (OF/NOR) test, affecting male mice only. Moreover, acute stress also reduced skin temperature and body weight in both females and males. We then injected Irisin into the hippocampus via bilateral stereotaxic injection and repeated the acute stress paradigm and combined OF/NOR test. We found that Irisin partially blocked stress-induced anxiety-like behavior and memory impairment in male mice, while also preventing the reduction in skin temperature and body weight. In females Irisin only prevented the body weight reduction but showed no beneficial effects on neurobehaviors. Our results suggest a novel role for Irisin in counteracting acute stress-induced neurobehavioral and physiological abnormalities. Also, our results support the idea that exercise can be a potentially effective tool to promote the maintenance of healthy neural function. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

FNDC4, a novel adipokine that reduces lipogenesis and promotes fat browning in human visceral adipocytes

BackgroundFibronectin type IIIdomain-containing protein 4 (FNDC4) constitutes a secreted factor showing a high homology in the fibronectin type III and transmembrane domains with the exercise-associated myokine irisin (FNDC5). We sought to evaluate whether FNDC4 mimics the anti-obesity effects of FNDC5/irisin in human adipose tissue. MethodsPlasma and adipose tissue samples of 78 patients with morbid obesity undergoing bariatric surgery and 26 normal-weight individuals were used in the present study. ResultsPlasma FNDC4 was decreased in patients with morbid obesity, related to obesity-associated systemic inflammation and remained unchanged six months after bariatric surgery. Visceral adipose tissue from patients with morbid obesity showed higher expression of FNDC4 and its putative receptor GPR116 regardless of the degree of insulin resistance. FNDC4 content was regulated by lipogenic, lipolytic and proinflammatory stimuli in human visceral adipocytes. FNDC4 reduced intracytosolic lipid accumulation and stimulated a brown-like pattern in human adipocytes, as evidenced by an upregulated expression of UCP-1 and the brown/beige adipocyte markers PRDM16, TMEM26 and CD137. Moreover, FNDC4 treatment upregulated mitochondrial DNA content and factors involved in mitochondrial biogenesis (TFAM, NRF1 and NRF2). Human FNDC4-knockdown adipocytes exhibited an increase in lipogenesis and a reduction of brown/beige-specific fat markers as well as factors involved in mitochondrial biogenesis. ConclusionsTaken together, the novel adipokine FNDC4 reduces lipogenesis and increases fat browning in human visceral adipocytes. The upregulation of FNDC4 in human visceral fat might constitute an attempt to attenuate the adipocyte hypertrophy, inflammation and impaired beige adipogenesis in the obese state.

Ejercicio y algunos mecanismos moleculares que subyacen a una mejora del desempeño en tareas cognitivas

Potenciar el aprendizaje y la memoria se ha convertido en una tarea de interés para muchos investigadores. Artículos recientes han podido comprobar es que el ejercicio es una clara herramienta para mejorar capacidades cognitivas de personas y animales gracias a que favorece la liberación de sustancias tales como neurotransmisores y factores neurotróficos. Uno de los factores más importantes es el factor neurotrófico derivado del cerebro (BDNF), que promueve la generación de cambios a nivel neuronal necesarios para la potenciación a largo plazo (fortalecimiento de memorias). Se realizó una búsqueda en las bases de datos de EBSCOhost -en las bases de Academic Search Complete, ERIC, MEDLINE, PsycARTICLES y SPORTDiscus-, Google Scholar, Pubmed y ScienceDirect utilizando una serie de palabras con sus respectivos criterios de inclusión y exclusión. En este trabajo se explican los procesos asociados con la potenciación a largo plazo, abarcando temas como neuroplasticidad, la unión del BDNF con su receptor (receptores de tirosina quinasa B), y además el mecanismo por medio del cual la liberación de la mioquina irisina, como una consecuencia del ejercicio, promueve el aumento de las concentraciones de BDNF en sangre. Basándose en numerosa literatura se describe la relación que existe entre el ejercicio y la generación de cambios neuroplásticos estimulados por proteínas como el BDNF y la consecuente mejoría en la memoria.

Myokine irisin curtails chondrocyte dysfunction and osteoarthritis through repressing WNT3A signaling

Purpose: Loss of chondrocytic activity, like repressed survival and extracellular matrix (ECM) underproduction, escalating articular cartilage damage in the development of osteoarthritis (OA). Moderate physical exercise is known to reduce the risk of OA of the knee. Myokine Irisin, a soluble and cleaved form of fibronectin type III domain containing 5 (FNDC5), is increased upon regular exercise regular and physical workout, regulating muscle strength, energy metabolism, skeletal homeostasis, and inflammation. Little is understood about whether this myokine changed ECM metabolism or cartilage integrity in OA joints remains uncertain. This study is aimed to investigate the Irisin action to chondrocyte survival and OA development. Methods: Articular cartilage specimens were harvested from patients with end-stage knee OA who required total knee arthroplasty and patients with femoral neck fracture who required total hip replacement. Knee joints in mice overexpressing FNDC5 were subjected to destabilized medial meniscus (DMM)-induced OA. Injured knees were intra-articularly injected with Irisin recombinant proteins. Articular cartilage integrity was quantified using OARSI scoring system. Osteophyte formation was probed using μCT scanning. Irisin, matrix metalloproteinases (MMPs), inflammatory cytokine and Wnt3a expression were probed with RT-quantitative PCR and immunohistochemistry. Results: Chondrocyte in human end-stage knee OA cartilage displayed weak FNDC5 immunostaining along with strong cell apoptosis marker TUNEL staining as compared to the non-OA group. Mice overexpressing FNDC5 showed mild OA signs, like cartilage degradation, adipose oveproduction, synovial hypercellularity, swelling and osteophyte formation in experimental OA models, along with improved gait profile of the injured legs. Likewise, intra-articular injection of Irisin recombinant protein downregulated chondrocyte apoptosis and cartilage matrix loss, as well as improved articular integrity and walking patterns of injured knees. In vitro, Irisin recombinant proteins attenuated MMP3, MMP9, IL-6 expression and apoptosis, whereas autophagy program and ECM proteoglycan production were preserved in inflamed chondrocytes. The IL-1β-augmented Wnt3a signaling was downregulated upon Irisin treatment. Conclusions: FNDC5 and Irisin losses are correlated with the development of human end-stage knee OA. The myokine maintains chondrocyte survival and ECM synthesis through repressing chondrocyte inhibitory factor Wnt3a to control autophagic and apoptotic programs. This study sheds new light onto the protective action of Irisin to chondrocyte function and articular integrity in the development of OA. Profound analysis also provides the prospective of therapeutic potential of Irisin recombinant protein for slowing down knee OA development.

Associations of Preoperative Irisin Levels of Paired Cerebrospinal Fluid and Plasma with Physical Dysfunction and Muscle Wasting Severity in Residents of Surgery Wards.

Myokine Irisin has been proposed to regulate metabolic homeostasis, which is related to chronic diseases or physical activity. However, whether irisin levels in paired cerebrospinal fruid (CSF), plasma and their ratio of inpatients, could use as biomarkers, and be independently related to the varying physical dysfunction, muscle wasting severity and chronic diseases with varying severe degrees, remain largely elusive. We conducted an observational study to assess the independent associations between irisin levels in paired cerebrospinal fruid (CSF), plasma and their ratio, and the independence in activities of daily life (ADLs), muscle wasting severity and chronic diseases with varying severe degrees among elderly Chinese in-patient subjects. Among 217 inpatients in surgery wards with a mean age of 68.07 years (±15.94years), 31.3% of women and 68.7% of men were included in the study. Bivariate correlation analysis showed that Log transformed CSF and plasma irisin levels and their ratio were potential associated with age, fat%, muscle wasting time, ADLs, number of multimorbidity, the severity of bone mass loss and anemia. Regression models analysis indicated that CSF and plasma irisin levels and their ratio in inpatient individuals were independently associated with the independence in ADLs. Plasma irisin levels were independently related to the change of muscle wasting use. Collectively, the evaluation of paired plasma and CSF irisin levels, and their ratio in in-patient individuals is intriguing candidates for the susceptibility of the independence in ADLs. Plasma irisin levels were positively associated with indepedence in ADLs, negatively related to muscle wasting severity, and could use as biomarkers for muscle wasting severity.

Characterization of Skeletal Muscle Endocrine Control in an In Vitro Model of Myogenesis

Skeletal muscle has remarkable regenerative abilities regulated by a highly orchestrated process involving the activation of cellular and molecular responses, which are dependent on satellite cells. These cells maintain the stem cell population and provide numerous myogenic cells that proliferate, differentiate, fuse and lead to new myofiber formation for a functional contractile tissue. We have isolated and characterized satellite cells obtained from human biopsies and established an in vitro model of myogenesis, evaluating muscle regeneration, monitoring the dynamic increases of the specific myogenic regulatory factors and the final formation of multinucleated myofibers. As the skeletal muscle is an endocrine tissue able of producing many substances that can act on distant organs, and it can be physiologically modulated by a variety of hormones, we embarked in a project of characterization of muscle cell endocrinology machinery. The expression of a large array of hormone receptors was quantified during the process of myogenesis. The results obtained showed a significant and generalized increase of all the tested hormone receptors along the process of differentiation of human cultured cells from myoblasts to myocytes. Interestingly, also the production of the myokine irisin increased in a parallel manner. These findings point to the human cultured myoblasts as an ideal model to characterize the skeletal muscle endocrine machinery and its hormonal regulation.

Irisin: Still chasing shadows

ObjectiveConsiderable uncertainty remains regarding the veracity of measuring myokine irisin more than seven years after its original description. Unresolved issues include the nature of transcription of the irisin precursor fibronectin type III domain containing 5 (FNDC5) gene across species, the reliability of irisin levels measured with commercial enzyme-linked immunosorbent assays (ELISAs), and the overall validity of the recently published reference values for human serum measured with quantitative mass spectrometry. We utilized multiple species and measures to evaluate the robustness of commonly used reagents and methods for reporting irisin. MethodsAmplification of cDNA was used to assess the FNDC5 transcript patterns in humans and mice. The specificity and sensitivity of different irisin antibodies were examined via western blotting. Quantification of circulating native irisin was conducted with mass spectrometry using an absolute quantification peptide for irisin. ResultsWe show that there is a greater transcript diversity of human FNDC5 than currently annotated, but no indication of the expression of transcripts leading to a truncated form of irisin. Available irisin antibodies still bind to patterns of unspecific serum proteins, which compromise reliable measurements of irisin with ELISAs. Absolute quantification of irisin with labeled peptides by mass spectrometry is an advanced method but requires a multi-step sample preparation introducing uncontrollable variations in the measurement. ConclusionOur data represent an explicit warning against measuring circulating irisin using available methods. Measuring irisin is akin to chasing shadows.

Grape pomace extract supplementation activates FNDC5/irisin in muscle and promotes white adipose browning in rats fed a high-fat diet.

Irisin is a myokine regulated by peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) in the exercising skeletal muscle and released into the bloodstream after cleavage of FNDC5. Circulating irisin can up-regulate UCP-1 expression in white adipose tissue (WAT) promoting the formation of brown-like adipocytes. The aim of this study was to evaluate if supplementation with a grape pomace extract (GPE) could activate the FNDC5/irisin pathway via PGC-1α in rats fed a high fat diet (HFD). For this purpose we characterized the activation of: i. the FNDC5/irisin pathway and AMPK in skeletal muscle and ii. proteins involved in the formation of brown-like cells in epididymal WAT (eWAT). Consumption of the GPE activated the FNDC5/irisin pathway, increased AMPK phosphorylation in skeletal muscle and enhanced irisin plasma levels. In eWAT, the GPE increased the level of proteins involved in WAT browning, i.e. PGC-1α, PPARγ, PRDM16 and UCP-1. The GPE also prevented HFD-induced adipocyte hypertrophy and systemic insulin resistance. Consistently, in L6 myotubes, (-)-epicatechin (EC), a flavonoid abundant in the GPE, prevented palmitate-mediated downregulation of FNDC5/irisin protein expression and secretion, in part via PGC-1α activation. Consumption of the GPE, a winemaking residue rich in bioactive compounds, could be a beneficial strategy to counteract the adverse effects of Western style diets through the promotion of WAT browning.

Supplemental Material for Hippocampal Injection of the Exercise-Induced Myokine Irisin Suppresses Acute Stress-Induced Neurobehavioral Impairment in a Sex-Dependent Manner

Supplemental Material for Hippocampal Injection of the Exercise-Induced Myokine Irisin Suppresses Acute Stress-Induced Neurobehavioral Impairment in a Sex-Dependent Manner