Aerobic exercise–induced myokine irisin release: A novel strategy to promote neuroprotection and improve cognitive function

Challenges in the prevention and treatment of mild cognitive impairment associated with Alzheimer’s disease: Increased life expectancy due to advancements in medical care has given rise to an aging population, accompanied by a surge in the incidence of incurable neurodegenerative diseases (NDDs). These diseases primarily affect the cognitive and behavioral functions of older adults by impacting brain activity. Mild cognitive impairment (MCI) is a neurodegenerative condition that affects a significant portion of the population. Characterized by memory loss, MCI is believed to be an early indication of Alzheimer’s disease (AD) and is generally considered to be a transitional state between healthy aging and AD onset. Currently, 24 million people worldwide are affected by AD, a number projected to increase fourfold by 2050. By this date, the global population over 65 years is expected to be triple what it was in 2010, at nearly 1.5 billion individuals. While cognitive and behavioral impairment are the first clinical symptoms of AD, memory loss typically appears before clinical diagnosis—particularly in people over 65 years of age—due to progressive loss of neurons and synapses, mainly in the cortex and hippocampus. By the time, AD is clinically diagnosed, several pathological changes in the brain are already in progress, including oxidative stress, amyloid-β (Aβ) and tau protein accumulation, metabolism alterations, blood–brain barrier dysfunction, microbiota-gut-brain axis dysfunction, mitochondrial dysfunction, and neuronal apoptosis. In pathological studies, excessive neuroinflammatory response and injury lead to the depletion of neurons in terms of structure, function, or quantity, resulting in the impairment of learning, memory, and other cognitive functions. These effects result in the early stages of MCI, which is associated with AD (Amartumur et al., 2024).

Today, the clinical diagnosis of AD-related MCI relies on mainly subjective criteria and is complicated by significant variations within and between individuals. Distinguishing MCI from other conditions in the early stages of the disease can be difficult, hindering the prompt selection of optimal treatment strategies. While some of the motor impairments associated with NDDs can be effectively treated in the early stages, interventions that modify the course of the disease and treatments for disabling non-motor symptoms are still lacking. Although numerous treatment strategies have enabled considerable prevention of motor and non-motor impairments in various experimental injury models, clinically applicable treatment options or drugs promoting functional recovery are not yet available. There is hope for breakthrough strategies that can reliably halt or slow down AD progression, but it is essential to approach these with a certain amount of skepticism: in recent decades, several promising preclinical treatments for AD have failed to translate to clinical practice.

New possibilities involving exercise-induced myokines: Over the past decades, the beneficial effect of physical activity on the human body has been extensively researched and documented. Skeletal muscle is considered a secretory organ that releases numerous muscle factors in response to exercise to communicate with other organs (Pedersen, 2019). This idea led to the proposal of myokines, peptides produced by contracting muscle fibers that mediate the various physiological, metabolic, and immunological effects of exercise. Myokines are released through autocrine, paracrine, or endocrine mechanisms. During exercise, they communicate with multiple muscles and other organ systems, including the brain. Numerous studies have demonstrated that different types of exercise regulate genes responsible for synaptic plasticity, thereby strengthening and maintaining connections between neurons and facilitating the formation of new synapses, ultimately enhancing memory. Of particular note, exercise stimulates neurogenesis in the dentate gyrus of the hippocampus and influences the proliferation, size, and function of astrocytes (Pedersen, 2019). Furthermore, exercise triggers the release of neurotransmitters such as endocannabinoids, serotonin, dopamine, endorphins, and norepinephrine, all of which significantly impact brain function. Other investigations have revealed that exercise can delay the onset of through a range of biological mechanisms. These mechanisms include the attenuation of Aβ accumulation, the suppression of aberrant phosphorylation of tau proteins, the augmentation of brain-derived neurotrophic factor (BDNF) expression, the reduction of neuroinflammatory processes, and the promotion of neuroplasticity (Li et al., 2024; Wu et al., 2024). These findings suggest that promoting the activity of exercise-induced myokines could facilitate brain-targeting therapies for AD-associated MCI. In addition to elucidating the role of exercise during neurodegeneration, understanding the cellular and molecular mechanisms underlying the muscle-brain axis is also fundamental to uncovering novel therapeutic strategies for AD-associated MCI.

In this perspective, we focus on studies examining the role of aerobic exercise in cognitive impairments and neuroinflammation. We discuss current and future therapeutic approaches to directly target myokines, either by inhibiting neuroinflammatory responses or by stimulating neuroprotective signaling mechanisms during the disease. We also discuss the need to consider bidirectional communication between exercise-induced myokines and the brain, as the therapeutic targeting of one is likely to alter the functions of the other.

Muscle–brain axis: Robust evidence linking exercise to brain health suggests a connection between muscles and the brain, but which peripheral mechanisms in the body trigger these positive effects of exercise is not entirely understood. However, nearly two decades of research have shown that skeletal muscle acts as a secretory organ. During exercise, skeletal muscles are highly active and communicate with other organs by producing and releasing myokines. There are hundreds of myokines, which are secreted during muscle cell growth, differentiation, or in response to muscle contractions. They can have effects within the muscle cell (autocrine), on neighboring cells (paracrine), or distant cells and tissues (endocrine). Some myokines help supply energy during acute phases of exercise, and multiple exercise sessions are likely to help the body adapt to training (Horowitz et al., 2020).

Recent studies have proposed the concept of the “muscle-brain axis,” demonstrating bi-directional communication between muscle and brain function (Pedersen, 2019; Arosio et al., 2023). Over the last few years, various forms of physical exercise have been proposed to exert neuroprotective effects and have emerged as promising therapeutic approaches against aging and NDDs. Muscle contraction plays a crucial role in regulating myokine expression, leading to increased levels in the bloodstream. Research suggests that the release of myokines triggered by exercise facilitates communication between the brain and muscles (Arosio et al., 2023). Furthermore, recent research has shown that transfusions of blood plasma from mice that have undergone exercise can induce the positive effects of exercise in both young and old mice, as well as in mouse models of AD pathology. This demonstration of effects on the brain and cognitive function provides the first link between muscles and AD etiology. It has been suggested that many of these beneficial effects of exercise on the brain are facilitated, to some extent, by the induction of BDNF (Horowitz et al., 2020). Thus, the exercise-induced beneficial impact on neurogenesis, cognitive function, appetite, and metabolism might—at least in part—be mediated by myokine signaling. Exercise-induced alteration in metabolites is another possible mediator of the effects of exercise on the brain (Horowitz et al., 2020). Together with circulating myokines and other molecules produced and released by skeletal muscle in response to exercise, direct feedback from skeletal muscle through the peripheral nervous system to the brain may also be involved in muscle-to-brain communication.

Aerobic exercise–induced myokines: FNDC5/Irisin reduces the severity of Alzheimer’s disease–associated mild cognitive impairment: Irisin, a novel myokine synthesized by adipose tissue and skeletal muscle, has been identified as a potential factor contributing to the beneficial effects of exercise on human health. It is the secreted form of the fibronectin type III domain-containing protein 5 (FNDC5), a transmembrane glycoprotein particularly abundant in skeletal muscle, the heart, and the brain. The expression of FNDC5 is regulated by the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), which is, in turn, stimulated by exercise. Accumulating evidence indicates that PGC-1α plays a crucial role in the positive effects of exercise on this tissue.

Initially identified as promoting mitochondrial biogenesis and oxidative metabolism in brown fat, PGC-1α has also been found to be essential in the brain. Studies have demonstrated that upregulation or overexpression of PGC-1α mitigates neurodegeneration, synaptic loss, and cognitive failure in different animal models of AD (Azimi et al., 2018; Pedersen, 2019). The cleavage of FNDC5 at the ectodomain releases a soluble fragment called irisin, composed of 112 amino acids, which enters the bloodstream. Recently, studies have confirmed the detection of irisin in the Purkinje cells of the cerebellum and its distribution in the hippocampus, cerebral cortex, hypothalamus, and putamen. It is believed to play a role in the neuroprotective effects of exercise, facilitated by its wide distribution in various brain regions. The exercise induces PGC-1α in skeletal muscle, stimulating FNDC5 and subsequent BDNF expression in the brain. Irisin increases FNDC5 expression in the hippocampus, leading to modified gene expression in neurons and glial cells. This process impacts the differentiation of embryonic stem cells and enhances the expression of BDNF and other genes that protect the brain, thereby promoting synaptic plasticity, neuronal differentiation, and overall neuronal well-being. A recent study by Li et al. (2024) reported that 8 weeks of aerobic exercise elevated spontaneous alternation counts and activity duration within the novel arm, thereby enhancing spatial learning and memory abilities. This suggests a favorable enhancement in spatial cognition as well as learning and memory abilities attributable to aerobic exercise. Similar investigation also demonstrated that moderate treadmill exercise mitigates the spatial learning and memory deficits induced by Aβ_1–42, which was concomitantly associated with enhanced AMP-activated protein kinase (AMPK) activity and the upregulation of the PGC-1α/ FNDC5/ BDNF signaling pathway (Azimi et al., 2018). Activation of the PGC-1α/FNDC5/BDNF axis assists in countering neurodegeneration and cognitive impairment.

Exercise can be a potent non-pharmacological intervention for the prevention of disease progression. Evidence suggests that the interaction of the motor system and cognitive functions under load may be a common mechanism through which exercise enhances working memory. However, the diverse motor and cognitive demands of different exercise types raise questions about the universal effects of exercise. While there are several concepts for categorizing exercise types, their practical application is limited due to a lack of specific details on interventions in studies analyzing the impact of exercise on working memory.

We recently reported that low-intensity aerobic exercise may increase circulating irisin levels, allowing it to cross the blood–brain barrier and reach the brain. In addition to these synergistic effects, aerobic exercise as an intervention was by itself sufficient to improve spatial memory learning and cognitive function; it also enabled slight but significant improvement in functional recovery after stimulating lipopolysaccharide (LPS) treatment in amnesic mice (Choi et al., 2024). Mechanically, we found that aerobic exercise is crucial for myokine secretion by investigating the protein expression of exercise-induced myokines such as FNDC5/irisin and BDNF in amnesic mice stimulated with LPS. Moreover, our results demonstrated that FNDC5/irisin is reduced in the hippocampus and cerebral cortex of the amnesic mouse. Aerobic exercise–induced FNDC5/irisin is directly correlated with BDNF expression in the brain. Finally, LPS-mediated impairment of spatial learning and cognitive function in amnesic mice is accompanied by down-regulation of brain FNDC5 expression (Choi et al., 2024). Together, these results indicate that irisin/FNDC5 might play a role in memory formation and neuronal protection and suggest that reduced brain irisin/FNDC5 levels may participate in the memory and cognitive deficits of amnesic mice (Figure 1). Accordingly, aerobic exercise-induced increases in irisin/FNDC5-mediated BDNF expression result in increased activation of cAMP response element-binding protein by phosphorylation and stimulation of antioxidant response proteins such as Nrf2 and HO-1; this activity favors new memory formation and neuronal survival (Choi et al., 2024).

Figure 1.

Schematic model showing research and treatment of aerobic exercise–induced myokine irisin/FNDC5 in MCI associated with AD.

Aerobic exercise can induce FNDC5 expression in skeletal muscles. The FNDC5 protein is then cleaved into irisin, which enters the circulating blood. Irisin can enter the brain by crossing the BBB, triggering BDNF synthesis and improving cognitive function. Irisin-mediated BDNF increase can also decrease neuroinflammation and microglial activation by reducing the production of NF-κB and pro-inflammatory cytokines through the activation of the CREB and Nrf2/HO-1 signaling pathways. Thus, aerobic exercise-mediated irisin release into the bloodstream can improve cognitive function by reducing neuroinflammation, inhibiting microglial activation, and neuronal apoptosis. Created with BioRender.com. AD: Alzheimer’s disease; BBB: blood-brain barrier; BDNF: brain-derived neurotrophic factor; COX-2: cyclooxygenase-2; CREB: cAMP-response element binding protein; FNDC5: fibronectin type III domain-containing protein 5; HO-1: heme Oxygenase 1; iba-1: ionized calcium-binding adapter molecule-1; IL-10: interleukin-10; IL-1β: interleukin-1 beta; iNOS: inducible nitric oxide synthase; MAPK: mitogen-activated protein kinase; MCI: mild cognitive impairment; NF-κB: nuclear factor kappa B; Nrf2: nuclear factor erythroid 2‐related factor 2; PGC-1α: proliferator-activated receptor gamma coactivator-1α.

Choi et al. (2024) also reported results that raise hope for the potential beneficial effects of aerobic exercise on inhibiting the microglial-mediated neuroinflammatory response. Analysis of mRNA expression in the hippocampus and cerebral cortex revealed that levels of inflammatory mediators (inducible nitric oxide synthase and cyclooxygenase-2) and cytokines (interleukin-1β, interleukin-10, and interferon-γ) were significantly elevated in LPS-activated amnesic mice. Microglia play a prominent role in neuroinflammatory processes and modulate the levels of inflammatory mediators and cytokines in the brain. We further examined the protein and mRNA expression of the microglial activation markers Iba-1 and GCN5 in the hippocampus and cerebral cortex of amnesic mice, finding them to be elevated compared to controls. Interestingly, aerobic exercise-mediated irisin/FNDC5 expression attenuates brain neuroinflammation and microglial activation and improves hippocampal learning and memory by increasing the expression of BDNF. Whether a reduction of neurotoxic activities in astrocytes by aerobic exercise also contributes to the inhibition of neuroinflammatory responses is currently unknown and remains to be investigated.

Beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) mediates amyloid precursor protein cleavage and Aβ formation, leading to neuronal degeneration and subsequently influencing memory and cognitive function. Inhibiting BACE-1 expression enhances levels of BDNF and reduces the formation of Aβ aggregates and associated neurotoxic proteins (Zagaar et al., 2012; Dao et al., 2013). Moreover, irisin/FNDC5 may also directly interact with amyloid precursor protein and decrease BACE-1 activity and Aβ formation (Noda et al., 2018). Treatment with irisin was shown to inhibit neurotoxin-induced mitochondria-dependent apoptosis by increasing Bcl-2 levels, decreasing Bax levels, and cleaving and activating caspase-3 (Zhang et al., 2023). Consistent with these effects, we found that the aerobic exercise intervention further produced irisin/FNDC5-mediated recovery of the elevated levels of BACE-1 expression. It also enhanced anti-apoptotic Bcl-2 levels and mitigated the adverse effects of Bax, caspase-3, and PARP-1 activation (Choi et al., 2024). These effects provide cause for optimism that aerobic exercise might aid neuron regeneration and improve cognitive function.

Microglia are highly heterogeneous in their phenotype and function, and they play essential roles in NDDs, repair, and aging. The presence of irisin receptors on microglia remains inconclusive. While Wang et al. (2022) reported the expression of the integrin β5 subunit irisin receptor in microglia, Chen et al. (2020) observed its expression in astrocytes but not microglia of AD patients. In cognitively intact individuals, neither astrocytes nor microglia expressed integrin β5. Additionally, exercise has been shown to convert adipose-resident macrophages from a pro-inflammatory M1 state to an anti-inflammatory M2 state, thereby reducing inflammation (Kawanishi et al., 2010). Therefore, it is crucial to investigate the impact of irisin on microglial activation and function in NDDs, as well as its role in mediating the exercise-induced effects on neuroinflammation-targeting microglia. However, there is limited research on irisin and its potential therapeutic role in the inhibition of microglia and p38MAPK-NF‐κB signaling activation in BV-2 microglial cells. Choi et al. (2024) recently demonstrated that irisin treatment inhibited the expression of inflammatory mediators such as inducible nitric oxide synthase, cyclooxygenase-2, and p38MAPK-NF‐κB-mediated upregulation of the Nrf2/HO-1 signaling pathway, which was possibly the result of reduced microglial activation. Our in vitro results are consistent with our in vivo study. We observed that aerobic exercise reduces the levels of iba-1 expression by inducing irisin/FNDC5 expression in the brain. This result indicates that aerobic exercise-induced irisin/FNDC5 expression hinders microglial activation and inflammatory responses.

In summary, the data provided by Choi et al. (2024) demonstrate that aerobic exercise is a promising non-pharmacological management option for people in the early stages of AD or who are experiencing memory or cognitive problems. Moreover, exercise-induced myokine irisin/FNDC5 is an important emerging therapeutic target for treating or preventing NDDs, including AD-associated MCI. Although we need more research to fully understand the impact of aerobic exercise on AD in humans, our data indicate that aerobic exercise can boost the production of irisin/FNDC5 in the brain. This effect can enhance memory and cognitive function by increasing neuroprotective signals, regulating neuroinflammatory responses, and reducing neuronal apoptosis. These findings suggest that aerobic exercise may be an effective treatment option for NDDs, including MCI associated with AD.

Limitations: A significant problem in selecting efficient exercise interventions is determining the most effective type and “dose” of exercise. This determination involves creating personalized training plans that consider an appropriate exercise type, intensity, volume, and session frequency. Personalized training plan prescriptions must be tailored to individual characteristics, including the specific capabilities and limitations of AD patients, and this should be investigated in the future. Additionally, the exact timing of irisin secretion after exercise has not been determined. Research on the duration of irisin levels’ return to baseline is essential. More efforts are needed to elucidate the molecular content of irisin secretion from different sources and clarify their impact on muscle-brain axis transmission under healthy and pathological conditions. Additional research is necessary to identify the specific receptors for irisin within the brain. Further investigation is required to identify new skeletal muscle-derived myokines that have a direct interaction with the CNS and the brain. Finally, more research is needed to evaluate how factors such as age, gender, and the type of physical exercise influence irisin and brain health and function.

This work was supported by The Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (RS-2023-00244901) (to RB).

Additional file: Open peer review report 1 ^{(106.7KB, pdf)} .