Irisin: A bridge between exercise and neurological diseases

Abstract

Exercise plays a beneficial regulating role on each organ of the body through different mechanisms and is a powerful weapon to prevent disease. Irisin is released from muscle and widely distributed in the human body, participating in the physiological processes of multiple human systems and playing a protective role in multiple human organs. The protective effect of irisin on the nervous system is particularly remarkable, which can improve cognitive function, reduce the risk of ischemic stroke and improve its prognosis. Irisin also plays a guiding role in the prevention and treatment of neurodegenerative diseases and ischemic cerebrovascular diseases. Exercise is the driving factor promoting irisin secretion, and different exercise modes, intensity, frequency, and time all affect the level of serum irisin. As a result of analyzing the effects of various exercise modes on irisin secretion, we proposed an exercise program with a higher level of irisin secretion.

Irisin; Exercise; Neurological diseases.

1. Introduction

In 2012, Pontus Bostrom et al. [1] discovered a new muscle cytokin called Irisin, named after the Greek goddess Iris. Specifically, irisin is a cleaved and secreted fragment of fibronectin type III domain-containing 5 (FNDC5) (FRCP2 and PeP) [2]. Irisin is widely distributed in the body. Previous study [3] has confirmed that irisin immune response is expressed in three types of cells by immunohistochemistry: skeletal muscle, cardiac muscle, and cerebellum Purkinje cells. Further studies showed that irisin was distributed in the skin, testis, pancreas, mammary gland, spleen, and stomach [4, 5, 6, 7, 8]. Pontus Bostrom et al. [1] also proposed that exercise can induce irisin secretion, stimulate the Browning of white adipose tissue and uncoupled protein 1 (UCP1) expression, increase overall energy consumption and improve obesity-related insulin resistance. In addition, irisin has biological effects such as regulating depressive behavior [9], proliferating osteoblasts [10], and cortical bone mass [11]. Irisin plays a positive protective role on the nervous system and can regulate some risk factors of Alzheimer's disease [12], including neurogenesis, oxidative stress, insulin resistance, and neurotrophic factor imbalance. Irisin can cross the blood-brain barrier, induce brain-derived neurotrophic factor (BDNF) secretion and participate in the regulation of synaptic plasticity [13]. During cerebral ischemia-reperfusion, irisin regulates BDNF expression in rodent stroke models, suggesting that irisin plays a beneficial role through BDNF in ischemic stroke [14]. It is predicted that about 72% of irisin comes from muscle secretion, and the remaining 28% may come from adipose tissue [1, 15], so exercise may be the most effective inducer of irisin secretion at present.

When the skeletal muscle contracts, irisin is produced. Hecksteden et al. [16] discovered that after 26 weeks of exercise training in relatively healthy people aged 30–60 years, there was no increase in circulating irisin. However, more and more studies [17, 18] on irisin have confirmed that exercise can promote the secretion of circulating irisin. A recent meta-analysis [19] found that physical activity had a significant and positive effect on serum irisin levels. Exercise stimulates the secretion of circulating irisin, a complex process involving numerous factors. We all know that exercise is good for brain health. At the same time, irisin also plays a protective role on the nervous system through various biological mechanisms. However, exercise-induced irisin secretion is related to many factors. How to maximize irisin secretion through exercise, to better protect the nervous system, and prevent and improve the prognosis of neurological diseases, is worth our in-depth study.

2. Effect of exercise on irisin secretion

2.1. Exercise frequency

Kraemer et al. [20] discovered that both men and women experienced a temporary increase in irisin concentration during the first hour of prolonged aerobic exercise in a study of young healthy men and women. Huh et al. [21] discovered that an increase in serum irisin concentration occurred as soon as 30 min after the end of the exercise, but not after 8 weeks of training. A study [22] of whole-body vibration exercises in healthy women discovered that acute whole-body vibration exercises can significantly increase circulating irisin levels. Long-term exercise did not raise baseline irisin levels, but it did increase exercise-induced irisin secretion [22]. Later, after excluding the effect of diet, some researchers [23] proposed that long-term military training increased baseline irisin levels, but their study only included men. These studies demonstrated that acute aerobic exercise can improve irisin concentration in circulation immediately, whereas long-term aerobic exercise can improve irisin metabolic kinetics and secretion efficiency. Interestingly, after Bubak et al. [24] proposed that the expression of circulating iris protein and skeletal muscle FNDC5 mRNA in humans after exercise were not affected by exposure to different ambient temperatures, Ozbay et al. [25] suggested that cold exposure would promote irisin secretion during long-term aerobic training. Simultaneously, Mu et al. [26] discovered that the regulation of cold exposure on irisin was related to individual exercise status, and that in a cold environment, the irisin secretion of people with a certain exercise basis would be weakened. Both exercise and cold exposure upregulate markers of Brown Adipose tissue (BAT) (e.g. UCP1 and PGC-1α) and BAT activators (e.g. iris protein, FGF21), but the upregulation of markers and activators is not entirely consistent, and the degree of upregulation depends on the intensity and duration of stimulus.

2.2. Mode of exercise

Tsuchiya Y et al. [27] proposed that, when comparing resistance exercise to endurance exercise and the combination of endurance and resistance exercise during the same exercise time, resistance exercise resulted in a more significant increase in irisin protein concentration. Scientists are attempting to understand how resistance training works. Reisi et al. [28] discovered through experiments that resistance exercise stimulates the expression of the FNCD5 gene, resulting in increased irisin levels. A later study [29] proposed that progressive resistance training can improve the level of circulating irisin in human subjects, improve muscle strength and function, and intervene in the aging-related decline in muscle function. Irisin secretion is, in fact, linked to aging. It has previously been reported that the baseline level of circulating irisin in the elderly is lower than in the young [30], and that the level of circulating irisin in children is significantly higher than in adults, indicating that irisin is independently negatively correlated with age [31]. Belviranli et al. [32] also proposed that long-term exercise can slow the decline in irisin levels caused by aging. However, age was not associated with exercise-induced irisin secretion. Kabak et al. [33] discovered that acute high-intensity interval training (HIIT) reduced circulating irisin concentrations in both sedentary people and athletes, with athletes experiencing a greater decrease. The latest study [34], however, suggests that HIIT-induced peak irisin concentrations are higher than moderate continuous intensity (MCI) exercise, particularly in healthy weight young adults. The inconsistency of the these studies' results could be attributed to a variety of factors, including the small sample size. In animal investigations, Murao et al. [35] confirmed that varied running patterns alter irisin secretion. Similar to prior research [36], in 60 overweight women, Amanat et al. [37] and Dianatinasab et al. [38] both did aerobic exercise (AE) and resistance exercise (RE). Three different training routines produced diametrically opposed results. Aria Dianatinasab et al. [38] concluded that there was no difference between the three exercise regimens, however Amanat et al. [37] claimed that AE and CE may better promote irisin secretion in overweight women. The major explanation for this outcome could be the irisin measurement time window. The exercise trial of Sasan Amanat et al. lasted 12 weeks, and baseline irisin concentration was tested 8 h before exercise, whereas the exercise trial endpoint of Sasan Amanat et al. was 8 weeks, and baseline irisin concentration was recorded 24 h before exercise. Based on these two tests, determining an exercise program suitable for overweight women remains difficult, and it should be investigated again after accurately controlling the time window of irisin concentration measurement in the future. To summarize, healthy young people can choose HIIT-like exercise methods to increase irisin secretion efficiency, whereas elderly people should do more resistance training.

2.3. Exercise intensity

Is it possible that varying exercise intensity plays a role in the complex process of exercise-induced irisin secretion? Tsuchiya et al. [39] recruited six men with similar exercise histories to participate in treadmill training at varying intensities but with the same energy expenditure. Exercise intensity has been shown in studies to influence irisin secretion. Regardless of energy expenditure during exercise, high-intensity exercise had a greater effect on irisin secretion in young men than low-intensity exercise. A larger study [40] involving both young men and women found that high-intensity exercise was the most effective at increasing irisin production. Furthermore, study of young men and women participating in moderate to high intensity swimming training support this view [30]. However, Winn et al. [41] proposed that the peak of irisin concentration in obese women, a special group of subjects who exercised in the afternoon, was higher during moderate-intensity exercise and lasted longer after exercise. As a result, the increase in irisin concentration is affected by a variety of factors, including the subjects' characteristics, the time point of the exercise, and the accuracy of the irisin concentration measurement. To summarize, choosing exercises with high exercise intensity based on one’s exercise ability is a good way to increase irisin secretion after exercise.

2.4. Metabolic abnormal population

Irisin is essential for glucose and lipid metabolism. Some researchers studied whether exercise can help people with metabolic syndrome secrete more irisin by using patients with metabolic syndrome as the target group and observing their serum irisin levels before and after exercise. Huh et al. [42] discovered that exercise could improve irisin levels in both groups, but there was no difference in the increase of irisin between the two groups when compared to the non-metabolic syndrome population. The above findings could be explained by irisin resistance in patients with metabolic syndrome and a small sample size. Effects of two types of exercise on irisin secretion in mice with and without metabolic syndrome were discussed by Tine et al [43]. It was discovered that the serum irisin level of mice with normal metabolism was higher than that of mice with abnormal metabolism, and the interaction between metabolic status and exercise program had an impact on irisin level in mice with normal metabolism. HIIT has a greater effect on irisin concentration in adipose tissue than continuous aerobic training (CMIT) under conditions of abnormal metabolism. Regardless of the exercise program, there was no difference in irisin concentration in skeletal muscle or serum. In people with metabolic abnormalities, exercise may be more effective at maintaining irisin concentrations in skeletal muscle and inducing the transport of circulating irisin into adipose tissue, and HIIT may enhance this effect. As a result, people with metabolic abnormalities should engage in HIIT more frequently.

The influence of diet combined with exercise on circulating irisin concentration was observed for one year in an experiment on exercise and lifestyle intervention for obese children, and it was discovered that circulating irisin concentration increased after adjusting diet and exercise [44]. Loffler et al. [31], on the other hand, stated that their long-term exercise study of children reached the opposite conclusion and considered possible correlations with subjects' body composition parameters, which they did not record. A recent study [45], however, discovered that after a one-year individualized, multidisciplinary exercise and diet intervention, overweight and obese children and adolescents experienced a decrease in irisin concentration as well as a decrease in Body Mass Index (BMI). A long-term aerobic training study in obese adults yielded similar results [46]. According to four different studies, body composition parameters may be closely related to the regulation of irisin secretion. To clarify the complex interaction between body composition parameters, exercise, and irisin, future studies should be more comprehensive in the design of exercise programs and the recording of body composition parameters.

2.5. Sex and circadian rhythm

It has previously been reported that irisin secretion differs between sexes. A study [47] of over 600 men and women found a negative correlation between irisin and exercise ability in men, but a positive trend between irisin and exercise ability in women. In a subsequent study [48], some researchers demonstrated that circulating irisin increased in the female population after acute anaerobic exercise, while there was no change in the male population, which seemed to support the previous study's conclusion. Huh et al. [21], on the other hand, performed acute sprinting training on 15 healthy men and discovered that circulating irisin concentration was increased 30 min after exercise. Kabasakalis et al. [49] also proposed that males had higher circulating irisin concentrations than females, both at rest and after aerobic exercise. In the future, the abnormal regulation of irisin secretion by gender should be investigated further, and exercise programs tailored to gender differences should be developed. According to Anastasilakis et al. [50], irisin secretion has a circadian rhythm, with the lowest at 6:00 a.m. and the highest at 9:00 p.m. Dennis Loffler [31], on the other hand, came to the opposite conclusion when he examined irisin secretion in young adults and children and discovered that irisin secretion does not have a circadian rhythm. The difference in results could be explained by the fact that the subjects evaluated by Athanasios D. et al [50] were soldiers with a higher level of physical health. As a result, for people who are physically active, morning exercise may be an effective way to improve circulating irisin concentration.

2.6. Effects of irisin on neurological diseases

As countries around the world, the pace of aging society gradually accelerated, the nervous system of age-related degenerative diseases, such as Alzheimer's disease (AD), and Parkinson's disease (PD), a dramatic increase in the prevalence of serious effects the quality of life for older people, brings a heavy burden to society and family, because there is no effective treatment, how to reduce the happening of this kind of disease, Slowing its progress is now a huge challenge for the medical community.

Exercise has many beneficial effects on the nervous system. A previous study [51] showed that irisin can regulate brain function through the blood-brain barrier in endurance sports. In this part, we sorted out how irisin plays a tandem role in motor and nervous system diseases.

2.7. Alzheimer’s disease

AD is a neurodegenerative condition marked by neurofibrillary tangles (NFTs), which are formed in the brain as a result of tau hyperphosphorylation and Ab deposition.

Islam et al. [52] demonstrated that Fndc5/irisin gene deletion impairs cognitive function in patients with Alzheimer's disease. In addition, after peripheral application of irisin in two different AD mouse models, they found that peripheral irisin would cross the blood-brain barrier and reach the brain, saving the cognitive decline that has undergone pathological changes.

Another animal study [53] also demonstrated that irisin prevents memory and cognitive deficits by regulating JAK/STAT and transcription 3(STAT3), as well as inflammatory damage in the brains of diabetic mice.

Kuster et al. [54] showed that irisin was significantly associated with episodic memory and global cognition in subjects at risk of dementia. Another clinical trial [55] found a positive correlation between irisin levels and neurophysiological performance in obese individuals with genetic risk of AD, and their neurocognitive deficits during visuospatial working memory tasks may be related to serum irisin.

Exercise can reduce the risk of dementia [56], which may be a sign of interaction between muscle and brain. The positive regulation of exercise-induced irisin secretion on AD cognitive dysfunction is one of the mechanisms behind this interaction. Lourenco et al. [57] found that FNDC5/irisin was expressed in the hippocampus, cerebral cortex, and cerebrospinal fluid of wild-type C57BL/6 mice, but at a lower level in AD mice. Wild-type mice whose brains had been knocked out of FNDC5/irisin performed poorly on new object recognition, radial arm water maze, and situational fear conditioning. In contrast, FNDC5/irisin injection into the lateral ventricle saved memory impairment in AD mice [6, 8]. Most importantly, if peripheral or cerebral FNDC5/irisin was blocked, the protective ability of physical exercise on the nervous system was also decreased [58].

One study [59] assessed cognitive function in rats through exercise training and found that age-induced cognitive impairment was associated with decreased expression of PGC-1α, FNDC5, and BDNF in the hippocampus, and that exercise activated the PGC-1α/FNDC5/BDNF pathway to prevent age-induced cognitive impairment. BNDF regulates synaptic plasticity and cognitive function [60].

The positive feedback of increased irisin secretion regulates the release of BNDF in the hippocampus. Belviranli et al. [61] also found that the BNDF and irisin levels and cognitive ability of endurance athletes were higher than those of sedentary people. Moreover, cognitive ability was positively correlated with BNDF and irisin, and irisin was also positively correlated with BNDF.

2.8. Parkinson’s disease

Parkinson’s disease is a movement disorder caused by the alteration and death of dopaminergic neurons in the substantia nigra. It is characterized by the accumulation of alpha-synuclein cytoplasmic protein, a major component of Lewy bodies, and is involved in the pathogenesis of Parkinson’s disease [62]. Parkinson’s disease is dominated by motor symptoms in the early stage, which are motor symptoms such as muscle rigidity and static tremor, and non-motor symptoms such as dementia and constipation gradually appear in the later stage.

Zarbakhsh et al. [63] treated rats with Parkinson's disease simultaneously with irisin and bone marrow stromal cells (BMSCs) and found that they could prevent the apoptosis and degeneration of dopaminergic neurons, and irisin could induce the migration of BMSCs in the damaged brain region, increase the number of tyrosine hydroxylase-positive neurons in the substantia nigra and striatum, and improve symptoms. Meanwhile, Rezaee, Z et al. [64] found that the levels of PGC1α, FNDC5, and BDNF were reduced in the striatum and hippocampus of PD mice induced by dopamine toxin. However, before induction, 16 weeks of running training on the treadmill could effectively prevent memory impairment, and the levels of PGC1α, FNDC5, and BDNF were reduced. More recently, physical activity in middle age has been shown to reduce the risk of Parkinson's disease in later life [65]. In conclusion, the alleviation of motor and non-motor symptoms in Parkinson's disease patients by exercise may be mediated by FNDC5/irisin, implying that irisin has a protective impact against the disease.

2.9. Stroke

Stroke is a serious disease with high rates of morbidity, mortality, and disability, and its incidence is age-dependent [66]. Ischaemic strokes (IS) account for roughly 80% of all strokes. Inadequate blood flow via brain vessels causes cerebral hypoxia, impaired glucose supply, and impaired elimination of superfluous metabolites, resulting in cerebral infarction. Despite advances in diagnostic and therapeutic methods, IS remains one of the leading causes of long-term disability in adults, as well as a leading cause of death [67]. Controlling disease-causing risk factors and improving disease prediction are critical ways to minimize the disability rate of IS.

Several animal experiments and clinical studies have proposed that irisin plays a neuroprotective role through different biological mechanisms and improves the neurological function of IS patients. Li et al. [68] found that serum irisin concentration in mice decreased after IS. In addition, irisin levels were negatively correlated with cerebral infarction volume, late neurological impairment, and TNF-ALPHA and IL-6 concentrations. Administration of recombinant irisin to diabetic mice reduced the size of cerebral infarcts and neurological deficits.

According to Yasin Asadi et al. [14], in a mouse model of experimental stroke, irisin reduces cerebral cortex cell death while boosting BDNF protein. Another study [69] in mice that generated global cerebral ischemia demonstrated that irisin improved neurological function and reduced apoptosis and neuronal damage.

Ischemic reperfusion may worsen brain injury in addition to the acute injury induced by hypoxia [70]. Yu et al. [71] discovered that irisin protects the mouse brain against is CHEMIa-reperfusion damage by modulating the TLR4/MyD88 pathway. Another animal study [72] found that irisin can prevent brain injury in terms of morphology and function, as well as protect the blood-brain barrier from damage following localized cerebral ischemia/reperfusion by reducing matrix metalloproteinase-9 (MMP-9) production and activity in brain tissue.

Tu et al. [73] conducted a multi-center experimental study on the correlation between irisin concentration and the prognosis of ischemic stroke with large sample size. They found that lower irisin concentration was associated with poor functional prognosis of ischemic stroke patients. Another study [74] involving 324 Chinese patients with ischemic stroke also found that low serum irisin levels were a predictor of poor early functional outcomes in patients with ischemic stroke.

More than 50 percent of stroke patients also develop cognitive impairment, and about 10 percent of them will have dementia, which severely affects their prognosis and quality of life [75, 76]. Zhao et al. [77] found that Swimming can improve cognitive impairment in cerebral ischemia mice by promoting the secretion of irisin in brain tissue, and this exercise exerts a beneficial effect similar to that of exogenous irisin treatment. Moreover, exogenous irisin can reduce oxidative stress by up-regulating klotho expression, thus improving cognitive dysfunction after cerebral ischemia injury. Exercise-induced irisin secretion can not only indirectly control risk factors of IS, such as hypertension and hyperlipidemia, but also directly act on damaged neurons, protect the blood-brain barrier, reduce the poor prognosis of IS and reduce cognitive impairment.

2.10. Epilepsy

Epilepsy is a brain condition characterized by the recurrence of unprovoked seizures [78]. Cheng et al. [79] evaluated the effect of exogenous irisin on neuronal injury in Kainic acid (KA) -induced status epilepticus (SE) rats. They demonstrated that exogenous irisin treatment significantly increased the expression of brain-derived neurotrophic factor (BDNF) and uncoupling protein 2 (UCP2). Irisin also reduces the level of neuronal injury and mitochondrial oxidative stress, which may play a neuroprotective role through the BDNF/UCP2 pathway.

A cross-sectional study [80] discovered that children with idiopathic epilepsy, particularly those who had uncontrolled seizures, had considerably higher serum irisin levels than healthy controls. Serum irisin levels were found to be strongly positively connected with seizure intensity, Chalfont score, and epileptic duration, as well as a predictor of epileptic loss.

Another cross-sectional study [81] found a decrease in serum irisin levels in patients with drug-resistant TEMPORAL lobe epilepsy compared to healthy controls and temporal lobe epilepsy, but the difference was not statistically significant, possibly due to the different types of antiepileptic drugs used by the enrolled patients.

Previous research [81] has revealed that epileptic medications have an effect on serum irisin levels in rats, although the mechanism is unknown.

In conclusion, irisin does play a neuroprotective role on the damaged neurons in the epileptic state and maybe a warning factor for the loss of control of idiopathic epilepsy in children. However, more clinical trials and analyses of influencing factors such as age and type of antiepileptic drugs are needed to explore the neuroprotective and warning effects of irisin in epilepsy.

3. Discussion

Irisin is a kind of muscle cytokine secreted by exercise-induced skeletal muscle, which is affected by factors such as exercise frequency, exercise mode, and exercise intensity.

Acute exercise can increase the concentration of irisin in the blood immediately, whereas chronic exercise improves the metabolic kinetics and secretion efficiency of irisin. Resistance exercise and higher intensity exercise are also important for promoting effective irisin secretion. At the same time, the regulation of irisin secretion by age, gender, and metabolic status vary across populations.

The initial research direction of irisin mainly focuses on metabolic diseases. Recently, more and more animal experiments and clinical studies [82, 83] have proved that irisin plays an important role in the nervous system through different biological mechanisms, including the positive effect on the prevention of neurological diseases and the potential therapeutic effect.

However, the secretion of irisin and its protective effect on the nervous system is a complex process involving multiple factors. Many research findings are contradictory, which can be attributed to a variety of factors such as the selection of time points for irisin measurement after exercise, cleavage of irisin during storage, detection kit accuracy, and so on. All of these should be combined to form a unified standard in order to improve the accuracy of irisin concentration determination. Furthermore, some meta-analyses [84] suggested that the primary source of heterogeneity and bias was study design. To produce more comprehensive and accurate results, we need to design more carefully designed randomized controlled trials that control exercise patterns, intensity, and population characteristics.

The muscle-brain axis is an important carrying channel for exercise to exert beneficial effects on the brain, and irisin is the key factor. We should have a precise and practical exercise prescription to guide people with different characteristics to secrete as much irisin as possible, to try to reduce the incidence of neurological diseases and improve the prognosis.

We propose a potentially instructive exercise prescription: (1) both acute and chronic exercise is beneficial to irisin secretion, and (2) try to do more resistance training as you get older. (3) Young men who are overweight or obese should be more likely to do HIIT.

Declarations

Author contribution statement

All authors listed have significantly contributed to the development and the writing of this article.

Funding statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability statement

No data was used for the research described in the article.

Declaration of interest’s statement

The authors declare no competing interests.

Additional information

No additional information is available for this paper.