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Abstract In 2002, a transmembrane protein—now known as FNDC5—was discovered and shown to be expressed in skeletal muscle, heart, and brain. It was virtually ignored for 10 years, until a study in 2012 proposed that, in response to exercise, the ectodomain of skeletal muscle FNDC5 was cleaved, traveled to white adipose tissue, and induced browning. The wasted energy of this browning raised the possibility that this myokine, named irisin, might mediate some beneficial effects of exercise. Since then, more than 1000 papers have been published exploring the roles of irisin. A major interest has been on adipose tissue and metabolism, following up the major proposal from 2012. Many studies correlating plasma irisin levels with physiological conditions have been questioned for using flawed assays for irisin concentration. However, experiments altering irisin levels by injecting recombinant irisin or by gene knockout are more promising. Recent discoveries have suggested potential roles of irisin in bone remodeling and in the brain, with effects potentially related to Alzheimer’s disease. We discuss some discrepancies between research groups and the mechanisms that are yet to be determined. Some important questions raised in the initial discovery of irisin, such as the role of the mutant start codon of human FNDC5 and the mechanism of ectodomain cleavage, remain to be answered. Apart from these specific questions, a promising new tool has been developed—mice with a global or tissue-specific knockout of FNDC5. In this review, we critically examine the current knowledge and delineate potential solutions to resolve existing ambiguities. Graphical Abstract Graphical Abstract

Hypoxia is a potent inducer of skeletal muscle atrophy; however, the underlying molecular mechanisms remain incompletely defined. Irisin, a myokine derived from Fndc5, plays a critical role in maintaining muscle mass and function, while endoplasmic reticulum (ER) stress has been implicated in muscle degeneration. Here, we investigated the interplay between hypoxia-induced ER stress and irisin regulation in skeletal muscle. Transcriptomic analyses and weighted gene co-expression network analysis (WGCNA) identified Fndc5 and Hspa5 (encoding GRP78) as key genes within hypoxia-related modules, displaying a strong negative correlation. In vivo, mice exposed to hypoxia showed reduced Fndc5/irisin expression accompanied by significant GRP78 upregulation. In vitro, chemical hypoxia and pharmacological induction of GRP78 by HA15 consistently suppressed Fndc5/irisin levels and impaired C2C12 myotube formation. Gene-miRNA network analysis suggested a shared post-transcriptional link between HSPA5-centered ER stress and FNDC5-associated atrophy programs under hypoxia, with miR-34a-5p as a candidate regulator. Collectively, these findings demonstrate that GRP78-driven ER stress under hypoxic conditions disrupts irisin production, thereby accelerating skeletal muscle atrophy. This work highlights a mechanistic axis linking ER stress to irisin deficiency in hypoxia-induced muscle wasting and provides new insights into potential therapeutic targets.

Irisin, the circulating peptide originating from fibronectin type III domain-containing protein 5 (FNDC5), is mainly expressed by muscle fibers under peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) control during exercise. In addition to several beneficial effects on health, physical activity positively affects nervous system functioning, particularly the hippocampus, resulting in amelioration of cognition impairments. Recently, FNDC5/irisin detection in hippocampal neurons and the presence of irisin in the cerebrospinal fluid opened a new intriguing chapter in irisin history. Interestingly, in the hippocampus of mice, exercise increases FNDC5 levels and upregulates brain-derived neurotrophic factor (BDNF) expression. BDNF, displaying neuroprotection and anti-inflammatory effects, is mainly produced by microglia and astrocytes. In this review, we discuss how these glial cells can morphologically and functionally switch during neuroinflammation by modulating the expression of a plethora of neuroprotective or neurotoxic factors. We also focus on studies investigating the irisin role in neurodegenerative diseases (ND). The emerging involvement of irisin as a mediator of the multiple positive effects of exercise on the brain needs further studies to better deepen this issue and the potential use in therapeutic approaches for neuroinflammation and ND.

Background 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. Methods 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 2 mg/kg recombinant irisin was performed three times per week in ageing mice (14‐month‐old) for 4 months or in aged mice (22‐month‐old) for 1 month 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. Results 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. Conclusions 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.

Sedentary life style is considered to be an independent risk factor for many disorders, including development of type 2 diabetes, obesity, immune dysfunction, asthma, and neurological or coronary heart disease. Irisin is released from myocytes during physical activity, and acts as a link between muscles and other tissues and organs. This myokine is produced as a result of proteolytic cleavage of FNDC5 protein present in the membrane of myocytes. Secretion of irisin is regulated by N-linked oligosaccharides attached to the protein molecule. The two N-glycan molecules, which constitute a significant part of the irisin glycoprotein, regulate the browning of adipocytes, which is the most important function of irisin. A receptor specific for irisin has still not been discovered. In some tissues irisin probably acts via integrins, which are widely expressed transmembrane receptors. Many studies have confirmed the multifunctional role of irisin and the beneficial effects of this molecule on body homeostasis. Irisin reduces systemic inflammation, maintains the balance between resorption and bone formation, and modulates metabolic processes and the functioning of the nervous system. It suppresses the expression and release of pro-inflammatory cytokines in obese individuals and attenuates inflammation in adipose tissue. The impact of irisin on cancer cell proliferation, migration, and invasion has also been demonstrated in numerous studies, which proves its role in carcinogenesis. Owing to these pleiotropic and beneficial properties, irisin may be a potential option to prevent and treat civilization-related diseases which are, nowadays, considered to be the major health problems in Western societies.

Aging is an important risk factor for cardiovascular diseases, and aging‐related cardiac dysfunction serves as a major determinant of morbidity and mortality in elderly populations. Our previous study has identified fibronectin type III domain‐containing 5 (FNDC5) and its cleaved form, irisin, as the cardioprotectant against doxorubicin‐induced cardiomyopathy. Herein, aging or matched young mice were overexpressed with FNDC5 by adeno‐associated virus serotype 9 (AAV9) vectors, or subcutaneously infused with irisin to uncover the role of FNDC5 in aging‐related cardiac dysfunction. To verify the involvement of nucleotide‐binding oligomerization domain‐like receptor with a pyrin domain 3 (NLRP3) and AMP‐activated protein kinase α (AMPKα), Nlrp3 or Ampkα2 global knockout mice were used. Besides, young mice were injected with AAV9‐FNDC5 and maintained for 12 months to determine the preventive effect of FNDC5. Moreover, neonatal rat cardiomyocytes were stimulated with tumor necrosis factor‐α (TNF‐α) to examine the role of FNDC5 in vitro. We found that FNDC5 was downregulated in aging hearts. Cardiac‐specific overexpression of FNDC5 or irisin infusion significantly suppressed NLRP3 inflammasome and cardiac inflammation, thereby attenuating aging‐related cardiac remodeling and dysfunction. In addition, irisin treatment also inhibited cellular senescence in TNF‐α‐stimulated cardiomyocytes in vitro. Mechanistically, FNDC5 activated AMPKα through blocking the lysosomal degradation of glucagon‐like peptide‐1 receptor. More importantly, FNDC5 gene transfer in early life could delay the onset of cardiac dysfunction during aging process. We prove that FNDC5 improves aging‐related cardiac dysfunction by activating AMPKα, and it might be a promising therapeutic target to support cardiovascular health in elderly populations. FNDC5 is downregulated in aging hearts, and cardiac‐specific overexpression of FNDC5 or irisin infusion attenuates aging‐related inflammation, cardiac remodeling, and dysfunction. Mechanistically, FNDC5 activates AMPKα through blocking the lysosomal degradation of GLP‐1R.

The fibronectin domain-containing protein 5 (FNDC5), or irisin, is an adipo-myokine hormone produced during exercise, which shows therapeutic potential for conditions like metabolic disorders, osteoporosis, sarcopenia, obesity, type 2 diabetes, and neurodegenerative diseases, including Alzheimer’s disease (AD). This review explores its potential across various pathophysiological processes that are often considered independent. Elevated in healthy states but reduced in diseases, irisin improves muscle–adipose communication, insulin sensitivity, and metabolic balance by enhancing mitochondrial function and reducing oxidative stress. It promotes osteogenesis and mitigates bone loss in osteoporosis and sarcopenia. Irisin exhibits anti-inflammatory effects by inhibiting NF-κB signaling and countering insulin resistance. In the brain, it reduces amyloid-β toxicity, inflammation, and oxidative stress, enhancing brain-derived neurotrophic factor (BDNF) signaling, which improves cognition and synaptic health in AD models. It also regulates dopamine pathways, potentially alleviating neuropsychiatric symptoms like depression and apathy. By linking physical activity to systemic health, irisin emphasizes its role in the muscle–bone–brain axis. Its multifaceted benefits highlight its potential as a therapeutic target for AD and related disorders, with applications in prevention, in treatment, and as a complement to exercise strategies.

The positive effects of physical exercise (EX) are well known to be mediated by cerebral BDNF (brain-derived neurotrophic factor), a neurotrophin involved in learning and memory, the expression of which could be induced by circulating irisin, a peptide derived from Fibronectin type III domain-containing protein 5 (FNDC5) produced by skeletal muscle contraction. While the influence of EX modalities on cerebral BDNF expression was characterized, their effect on muscle FNDC5/Irisin expression and circulating irisin levels remains to be explored. The present study involved Wistar rats divided into four experimental groups: sedentary (SED), low- (40% of maximal aerobic speed, MAS), intermediate- (50% of MAS) and high- (70% of MAS) intensities of treadmill EX (30 min/day, 7 days). Soleus (SOL) versus gastrocnemius (GAS) FNDC5 and hippocampal BDNF expressions were evaluated by Western blotting. Additionally, muscular FNDC5/Irisin localization and serum/hippocampal irisin levels were studied by immunofluorescence and ELISA, respectively. Our findings revealed that (1) serum irisin and hippocampal BDNF levels vary with EX intensity, showing a threshold intensity at 50% of MAS; (2) hippocampal BDNF levels positively correlate with serum irisin but not with hippocampal FNDC5/Irisin; and (3) GAS, in response to EX intensity, overexpresses FNDC5/Irisin in type II muscle fibers. Altogether, peripheral FNDC5/Irisin levels likely explain EX-dependent hippocampal BDNF expression.

Nicotinamide adenine dinucleotide (NAD )-boosting therapy has emerged as a promising strategy to treat various health disorders, while the underlying molecular mechanisms are not fully understood. Here, we investigated the involvement of fibronectin type III domain containing 5 (Fndc5) or irisin, which is a novel exercise-linked hormone, in the development and progression of nonalcoholic fatty liver disease (NAFLD). NAD -boosting therapy was achieved by administrating of nicotinamide riboside (NR) in human and mice. The Fndc5/irisin levels in tissues and blood were measured in NR-treated mice or human volunteers. The therapeutic action of NR against NAFLD pathologies induced by high-fat diet (HFD) or methionine/choline-deficient diet (MCD) were compared between wild-type (WT) and mice. Recombinant Fndc5/irisin was infused to NALFD mice via osmotic minipump to test the therapeutic action of Fndc5/irisin. Various biomedical experiments were conducted and to know the molecular mechanisms underlying the stimulation of Fndc5/irisin by NR treatment. NR treatment elevated plasma level of Fndc5/irisin in mice and human volunteers. NR treatment also increased Fndc5 expression in skeletal muscle, adipose and liver tissues in mice. In HFD-induced NAFLD mice model, NR displayed remarkable therapeutic effects on body weight gain, hepatic steatosis, steatohepatitis, insulin resistance, mitochondrial dysfunction, apoptosis and fibrosis; however, these actions of NR were compromised in mice. Chronic infusion of recombinant Fndc5/irisin alleviated the NAFLD pathological phenotypes in MCD-induced NAFLD mice model. Mechanistically, NR reduced the lipid stress-triggered ubiquitination of Fndc5, which increased Fndc5 protein stability and thus enhanced Fndc5 protein level. Using shRNA-mediated knockdown screening, we found that NAD -dependent deacetylase SIRT2, rather than other sirtuins, interacts with Fndc5 to decrease Fndc5 acetylation, which reduces Fndc5 ubiquitination and stabilize it. Treatment of AGK2, a selective inhibitor of SIRT2, blocked the therapeutic action of NR against NAFLD pathologies and NR-induced Fndc5 deubiquitination/deacetylation. At last, we identified that the lysine sites K127/131 and K185/187/189 of Fndc5 may contribute to the SIRT2-dependent deacetylation and deubiquitination of Fndc5. The findings from this research for the first time demonstrate that NAD -boosting therapy reverses NAFLD by regulating SIRT2-deppendent Fndc5 deacetylation and deubiquitination, which results in a stimulation of Fndc5/irisin, a novel exerkine. These results suggest that Fndc5/irisin may be a potential nexus between physical exercise and NAD -boosting therapy in metabolic pathophysiology.