Exercise Regulates Myokines in Aging-Related Diseases through Muscle-Brain Crosstalk

In recent years, aging has gradually become a significant problem worldwide, prompting an increasing number of researchers to focus on the safety and quality of life of the elderly population [1]. As the body ages, somatic health and cognitive health are damaged, and a variety of chronic diseases occur. Skeletal muscle and brain age earlier than organs such as the liver. Skeletal muscles will experience problems such as loss of muscle mass and strength, and the brain will gradually shrink with age. In addition, because brain nerve cells and skeletal muscle cells are permanent cells in the body that only increase and do not decrease, skeletal muscle and the brain tend to be more affected during aging. The prevalence of muscle-brain diseases such as sarcopenia and cognitive impairment is also high, affecting the safety and quality of life of the elderly and bringing a substantial economic burden on public health care [2‒5]. Moreover, studies have shown that sarcopenia can aggravate the decline in cognitive function in elderly individuals, and elderly individuals with sarcopenia are more likely to suffer from cognitive decline, cognitive impairment, and other brain-related diseases [6]. In addition, some scholars have found a significant correlation between Alzheimer’s disease (AD) and gait speed, which is one of the criteria for diagnosing sarcopenia, and it is also closely related to organic pathological changes in the brain [7]. This means that brain diseases such as AD may co-occur with skeletal muscle age-related diseases such as sarcopenia. Muscle-brain diseases are accompanied mainly by each other.

Exercise has been widely confirmed to promote the physical and mental health of elderly people. It also significantly affects some chronic diseases in elderly individuals, especially preventing and treating muscle-brain diseases. Many studies have shown that exercise has a positive effect on delaying the decline of cognitive function and motor function in older adults and can reduce the likelihood of their occurrence or slow down or reverse their progression [8‒12]. Exercise can reduce the loss of skeletal muscle mass, enhance skeletal muscle strength and endurance, and effectively prevent the occurrence of sarcopenia or delay its development. Exercise also has a significant effect on the brain. Studies have shown that exercise is beneficial to brain memory function, cognitive function, and emotional function and has a specific therapeutic effect on brain diseases such as AD [13‒15].

The dual role of exercise in muscle-brain diseases can be attributed to a substance that mediates between skeletal muscle and the brain, called a myokine. Myokines are soluble factors secreted by skeletal muscle, including polypeptides, growth factors, cytokines, and small organic acids, which scholars have proposed in recent years to explain and clarify the mechanism of exercise on chronic diseases in the elderly [16]. There are many studies on the mechanism of exercise prevention and treatment of chronic diseases in elderly individuals, and the current research on muscle-brain diseases is also increasing. Exercise physiology experts believe that skeletal muscle may produce myokines involved in the crosstalk between skeletal muscle and the brain [17‒20]. However, the interaction mechanism by which exercise regulates the expression of myokines to promote muscle-brain health and prevent muscle-brain diseases is unclear and lacks systematic combination. Therefore, this review summarizes the research evidence on the involvement of types of exercises regulating myokine levels through muscle-brain crosstalk in recent years, sorts out the key mechanism of action of exercise-regulating myokines influencing muscle-brain diseases, and observes the influence of different exercise types, intensities, and durations on the expression level of myokines, trying to find the most effective way of exercise to guide further understanding of the mechanism of exercise preventing and treating muscle-brain diseases in elderly individuals.

This study compares the effects of several exercise-regulated myokines on age-related diseases through muscle-brain interactions. We sought to examine the effects of changes in exercise type, duration, and intensity on myokine levels. Using the terms “myokine,” “myokines,” “exercise,” “training,” “physical activity,” “aging,” “brain,” and “muscle,” four were in English electronic databases (Web of Science, PubMed, EBSCO, OVID), and the rest were in Chinese electronic databases (China Knowledge Network). The literature search period was from July 2022 to February 2023. In addition, only articles published in English or Chinese for which the full text was available were included.

After a systematic search of five databases, we established inclusion and exclusion criteria. To be included in this article, the literature needed to be as follows: (1) published in English or Chinese; (2) associated with age-related diseases; (3) involving at least one of the following myokines (brain-derived neurotrophic factor [BDNF], insulin-like growth factor 1 [IGF-1], irisin, cathepsin B [CATB], interleukin 6 [IL-6], fibroblast growth factor 21 [FGF21], and vascular endothelial growth factor [VEGF]); (4) only humans or animals were used as experimental subjects; and (5) exercise as an intervention measure. References that met the following exclusion criteria were excluded: (1) noncontrolled or experimental articles; (2) missing data; (3) no complete abstract or article content; and (4) nonmuscle-brain interaction.

All the included studies were controlled trials, including 18 randomized and 6 nonrandomized controlled trials. For randomized controlled trials, the risk of bias and the quality of included literature were assessed by the “risk of bias tool” in the Cochrane Manual, including six aspects: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting. Each item evaluated as low risk would receive one point. The Methodological Index for Nonrandomized Studies (MINORS) was used to assess the quality of nonrandomized controlled trials. The MINORS instrument includes 12 items; four are only applicable to studies with control groups. Each item scores 2. When the total score is 24, a score greater than or equal to 17 indicates high quality.

In the process of literature retrieval, we took “myokine,” “myokines,” “exercise,” “training,” “physical activity,” “aging,” “brain,” and “crosstalk” and their combinations as keywords. A total of 2,941 articles were obtained. After removing duplicate articles, we further screened the titles and abstracts of the articles according to the keywords. After reading the complete text, we finally included twenty-four articles that met the inclusion criteria. The specific flowchart of literature screening is shown in Figure 1.

The literature included in this review dates from 2011 to 2022. Among the twenty-four articles, there were four from 2011 to 2012 (n = 4, 16.67%), two from 2013 to 2014 (n = 2, 8.33%), three from 2015 to 2016 (n = 3, 12.50%), and three from 2017 to 2018 (n = 3, 12.50%). There were four papers from 2019 to 2020 (n = 4, 16.67%) and eight from 2021 to 2022 (n = 8, 33.33%). A total of 7 common myokines were included in the literature, including eighteen articles about BDNF and four articles about IGF-1. There were three articles on CATB, four on irisin, four on VEGF, and five on IL-6. There are three articles about FGF21. The amount of literature on each myokine changing over time is shown in Figure 2. Details can be seen in online supplementary Figure 1 (for all online suppl. material, see https://doi.org/10.1159/000535339).

Finally, the literature included the use of human or animal research models. Four studies involved animal models, including rats (n = 1 Wistar rat) and mice (n = 2 C57BL/6 mice, n = 1 C57BL/6 N Hcar1 knockout and wild-type mouse). Of the two C57BL/6 mice, one was normal C57BL/6 mouse, and the other was Tg-NSE/htau23 and non-TG mouse. Of the literature using the human model, 11 included both males and females, and the remainder included only males (n = 4) or females (n = 6). Only one paper used both human and animal models. Different types of exercise interventions were used in the study (aerobic exercise [AE], n = 13; high-intensity interval training [HIIT], n = 1; high-intensity circuit training [HICT], n = 1; AE or resistance exercise [RE], n = 4; RE, n = 2; AE or combined AE and RE, n = 2; and combined AE and RE, n = 1). Four studies examined acute effects, with durations ranging from 1 day to 1 week. The remaining studies ranged from 3 weeks to 1 year, mostly 3 times per week. Two studies reported both acute and chronic effects. The characteristics of the included studies are summarized in Table 1.

The assessment results are shown in Table 2, 3. The literature in Table 2 all mentioned randomization, while six (31.6%) described the generation of the random sequence in detail [22, 24, 32, 34, 38, 40]. Four studies (21.1%) addressed the allocation concealment [22, 38, 40, 41]. Due to the particularity of exercise intervention, most studies used a single-blind or no-blind method. However, the study results showed that the concentration of myokines in blood or tissues was not affected by or minored by the blind method. In addition, most of the literature reported a low risk of selective reporting bias (n = 13, 68.4%), suggesting selection bias in the included studies. The scores in Table 3 range from 11 to 21, and four studies are considered high quality.

The literature included in this paper analyzed the changes in the levels of myokines such as BDNF, IGF-1, IL-6, and irisin after different exercise interventions, which involved age-related diseases such as AD, diabetes, metabolic syndrome, cognitive function decline, neuroinflammation, and metabolic disorders. BDNF can regulate the development and differentiation of new neurons and promote the survival of neurons, which has an excellent promoting effect on cognitive function. IL-6 mediates anti-inflammatory effects by inhibiting TNF-α and IL-1 and activating IL-1ra and IL-10. IL-6 plays a neurotrophic role as well as VEGF, while CATB and IGF-1 play a neuroprotective role. IGF-1 can also activate the cellular protein kinase pathway and phosphatidylinositol-3 kinase pathway, thus inhibiting cell apoptosis and reducing the possibility of neuropathic pathogenesis to prevent cognitive decline [45]. In addition, CATB has been shown to promote the expression of BDNF. Meanwhile, [45] found that IL-6 can increase the expression of BDNF, and the increase in BDNF in rats lacking IL-6 almost disappeared after nerve injury, suggesting that BDNF may be one of the mechanisms by which IL-6 affects nerve differentiation and occurrence [46, 47]. IGF-1, IL-6, and irisin regulate human metabolism by participating in glucose and fat metabolism. Irisin has an excellent anti-inflammatory effect and is beneficial to cognitive function. Studies have found that overexpression of irisin in the brain can save synaptic plasticity and memory defects in AD mouse models, and peripheral overexpression of irisin can promote the expression of BDNF. Some scholars believe that the cognitive benefits of irisin may be indirectly mediated by BDNF [47, 48]. Exercise can stimulate the production and release of these myokines. These myokines enter the circulation with the blood, directly or indirectly playing a role in nutrition and protection of the brain, promoting brain function, and delaying brain aging. At the same time, the brain acts on the muscles to better control and regulate muscle nutrition and blood supply, promote the function of skeletal muscle, make it better to complete exercise, promote the release of myokines, and delay the aging of skeletal muscle. The two promote each other to maintain muscle-brain health.

AE can promote the expression of most myokines, including BDNF, IL-6, VEGF, CATB, irisin, and IGF-1. Four studies reported increased BDNF concentrations after low- to moderate-intensity AE (p < 0.05) [21, 26, 27, 35]. Three studies used low-intensity AE interventions, two of which showed an increase in BDNF levels, and one showed a decrease [23, 31, 36]. Two showed an increase in the moderate-intensity intervention, while one showed no significant difference [29, 34, 37]. Notably, one study that divided participants into two groups (basic and advanced) achieved opposite results with the same intervention [25]. Two studies found an increase in CATB levels, and both chose a frequency of exercise 3 times a week with low- or moderate- to high-intensity interventions [24, 36]. Two studies involved levels of VEGF. One immediate exercise showed an increase, but the other long-term exercise showed no significant change, both at moderate intensity [29, 37]. Three of the four studies found elevated levels of IL-6 over a 12-week duration, with a frequency no more than 3 times a week, and at low, moderate, and moderate to high intensities (p < 0.05) [25, 35, 41]. However, one found a decrease in IL-6 levels at moderate to high intensities 5 times a week for 12 weeks [28]. Four involved levels of IGF-1, and two found that IGF-1 levels rose with moderate or moderate-to-high exercise no more than 3 times a week for no more than a week [34, 37]. In comparison, IGF-1 levels did not improve significantly after 3 months of moderate-intensity exercise 3 times a week [29]. Two studies found that irisin levels increased with 12 weeks of moderate-intensity exercise 3 times a week and 3 weeks of moderate- or high-intensity exercise once a week [25, 33]. One found an increase in FGF21 levels at low to moderate intensity 3 times per week for 6 weeks [30].

RE benefits the expression of some myokines, such as BDNF, irisin, IGF-1, and CATB. Three of the five studies found an increase in BDNF levels, two of which selected low- or low- to moderate-intensity exercise 3 times a week for 12 weeks [35, 36]. The other one was moderate-intensity exercise 3 times a week for 1 week [34]. The other two studies, however, found no significant change in BDNF levels after 22 weeks of low- to moderate-intensity exercise twice a week or an immediate moderate-intensity training [37, 38]. One study found that 12 weeks of low- to moderate-intensity exercise 2 to 3 times a week increased irisin levels [39]. Two studies looked at IGF-1 levels and found an increase at moderate intensity, one immediate and the other 3 times a week for 1 week [34, 37]. A study of low-intensity exercise 3 times a week for 12 weeks found increased CATB levels [36].

There are few studies on the effect of combined AE and RE, HIIT, and HICT on the expression of myokines, and it mainly affects the improvement of BDNF, VEGF, and IL-6. Three studies found that BDNF levels increased with 5 weeks of high-intensity cycle exercise 3 times a week and 12 weeks of moderate or moderate- to high-intensity exercise once a week [41, 42, 44]. Elevated levels of VEGF were found in two studies, one with high-intensity interval exercise 5 times a week for 7 weeks and the other with moderate-intensity combined AE and RE 3 times a week for 6 months [40, 43]. Two studies that included IL-6 levels found that IL-6 levels increased after high-intensity cycle exercise 3 times a week for 5 weeks and moderate- to high-intensity exercise once a week for 12 weeks [41, 44]. IL-6 levels were elevated when measured immediately after exercise. In addition, the levels of irisin, FGF21, and CATB were also found to be age-related during high-intensity cycle exercise. Irisin increased in the elderly group, while FGF21 and CATB decreased in the elderly group [44].

Exercise promotes skeletal muscle secretion and releases myokines. After being released, different myokines reach different positions in the body and exert their functions, such as anti-inflammatory, nutritional nerve, enriching blood vessels, and regulating metabolism, to promote body health and finally achieve the purpose of preventing and treating chronic diseases in the elderly [49‒53]. More than 600 myokines have been discovered, including decorin, BDNF, myostatin, IGF 1, and meteorin-like. The main myokines associated with muscle-brain diseases are BDNF, IGF-1, irisin, CATB, IL-6, FGF21, and VEGF. AD is the most common age-dependent neurodegenerative disease, characterized by the formation of senile plaques from β-amyloid (Aβ) deposits and neurofibrillary tangles from the accumulation of hyperphosphorylated tau proteins. Aβ is produced by amyloid precursor protein (APP) under the cleavage of β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase. In contrast, α-secretase competitively inhibits β-secretase activity and reduces Aβ production. It has been found that BDNF, IGF-1, and CATB are all effective in inhibiting Aβ production and accumulation. BDNF both enhances α-secretase activity and produces soluble APP α with neuroprotective properties and attenuates Aβ42-induced neuronal toxicity, mediating motor inhibition of BACE1 content and activity [54]. IGF-1, a key regulator of CNS neuronal function, enhances synaptic plasticity, increases synaptic density, inhibits Aβ production, and reduces neurofibrillary tangle formation and cerebral amyloidosis. The upstream agonist of the irisin precursor FNDC5, peroxisome proliferator-activated receptor gamma coactivator-1α, is rapidly activated under exercise stress conditions and inhibits Aβ production and accumulation by downregulating BACE1 levels [55, 56]. CATB accelerates Aβ metabolism via the lysosomal pathway [46]. In addition, IL-6 reduces oxidative stress in the body by exerting its anti-inflammatory effect, and VEGF inhibits Aβ-induced endothelial cell apoptosis [57, 58]. Sarcopenia is an age-related degenerative disorder with progressive loss of skeletal muscle mass and reduced muscle strength. There are four broadly accepted causes of sarcopenia, including aging-induced oxidative stress and mitochondrial dysfunction, activation of apoptotic signaling pathways in skeletal muscle cells, impaired autophagic flow due to low levels of cellular autophagy, and increased inflammatory cytokines [59‒62]. Exercise can improve muscle mass and function by promoting protein synthesis, decreasing inflammatory factors, inhibiting the expression of apoptotic factors in senescent muscle atrophy, increasing cellular mitochondrial mass, and enhancing metabolic enzyme activity [63‒65]. Therefore, myokines secreted by skeletal muscle after exercise can effectively prevent the occurrence of muscle-brain diseases such as AD and sarcopenia. The symptoms of muscle-brain diseases, such as cognitive decline, inflammation, and metabolic disorders, can also be alleviated through the anti-inflammatory, nutritional, and regulatory effects of myokines, thus delaying the development of the disease. All these myokines have nutritional and protective effects on the brain, enter the circulation with the blood, and then directly or indirectly promote brain function, delaying brain aging. Figure 3 is visible. However, different kinds of exercise may have different effects on myokines. It was found that stimulation of skeletal muscle cells is conducive to the secretion of CATB and BDNF, while continuous contraction of skeletal muscle is conducive to the secretion of IL-6 [47, 66]. At the same time, draft induction of skeletal muscle can promote IGF-1 secretion. When skeletal muscle is slightly damaged, VEGF secretion increases [67]. Irisin is formed by motion-induced cleavage of FNDC5. The anti-inflammatory, nutritional, and regulatory effects of these myokines work together to protect the brain. Furthermore, the brain controls and regulates muscle nutrition and blood supply, maintaining the normal physiological activities of skeletal muscle. A healthy brain can improve skeletal muscle function and complete activities, thus delaying skeletal muscle aging. The two promote each other to maintain muscle-brain health. It can be seen in Figure 4.

Currently, researchers mainly use AE and RE to study the mechanism by which exercise regulates myokines to prevent muscle-brain diseases. Combined exercise has also been mentioned, but AE is still the primary method. This study reviewed the studies on the levels of muscle-brain-related myokines regulated by different modes of exercise in recent years and attempted for the first time to systematically determine the critical mechanism of action of muscle-brain diseases regulated by exercise. At the same time, considering that different exercise prescriptions may have different effects on the expression levels of myokines, the exercise duration, intensity, and frequency were observed to summarize a more appropriate exercise prescription.

AE is the most commonly used exercise in the elderly population, and its effect on delaying aging has been widely confirmed. Studies have shown that AE can reduce the excessive degradation of muscle fiber proteins by regulating energy metabolism and autophagy in skeletal muscle mitochondria, thereby reducing muscle mass loss and strength decline and preventing muscle atrophy [68]. AE has also been shown to induce skeletal muscle to produce and release myokines. When skeletal muscle is slightly damaged and then repaired, VEGF and CATB are released into the blood; long-term contraction of skeletal muscle promotes IL-6 release; elongation induction of skeletal muscle promotes IGF-1 release; cleavage of FNDC5 in skeletal muscle produces irisin; and stimulation of skeletal muscle cells promotes BDNF release [47, 69, 70]. AE is effective in muscle-brain diseases. In addition to maintaining the normal reoxygen-reduction balance, preventing the ubiquitin-proteasomal system from increasing protein degradation, and preventing skeletal myopathy, myokines such as BDNF, CATB, IL-6, IGF-1, irisin, and VEGF produced by skeletal muscle have neurotrophic, vasotrophic, anti-inflammatory, and other effects, which can maintain and promote brain function, thereby delaying brain aging [71‒74]. IL-6 plays an anti-inflammatory role by inhibiting TNF-α and IL-1 and mediating the activation of IL-1ra and IL-10. IL-6 plays a neurotrophic role along with VEGF, CATB, and IGF-1. IGF-1 can also activate the cellular protein kinase pathway and phosphatidylinositol-3 kinase pathway to inhibit cell apoptosis and reduce the possibility of neuropathic pathogenesis to prevent cognitive decline. Irisin has good anti-inflammatory and cognitive functions, while BDNF regulates brain development and protects nerves. Brain diseases are generally caused by local inflammation, degenerative changes in the nervous system, reduced blood circulation, and other problems. For example, AD is characterized by Aβ protein precipitation and neuronal tangles and may also be affected by local inflammation, showing a decline in cognitive function. These myokines may play a neuroprotective, anti-inflammatory role in preventing the progression of AD before it is developed and may also slow the progression of the disease after it is developed and prevent it from worsening. Studies on AE intervention after cognitive decline also found that cognitive function tests such as the Morris water maze test and Stroop interference test showed better results than before [44, 75]. Current studies on exercise-regulating myokines mostly use exercise with a frequency of 3 times a week. This frequency was selected in 13 of the 19 articles involving the levels of myokines influenced by AE intervention. The results showed that the level of BDNF increased significantly after 12–48 weeks of exercise intervention at low to moderate intensity. The increase may be caused by prolonged stimulation of skeletal muscle, which yields cells to produce and release BDNF. In addition, the study of CATB levels also often uses an exercise frequency of 3 times a week. At the same time, the increase in the level of postexercise may be related to age. The results show that the CATB level of participants with an average age of 64.9 years or older increases significantly after exercise of different intensities ranging from 12 weeks to 26 weeks. Some scholars have found that running seems to induce skeletal muscle to release CATB by stimulating L6 myoblasts, but the exact process remains unclear [24, 46]. Three times a week is a good frequency for older adults, providing continuous motor stimulation and time for skeletal muscle rest and recovery. At the same time, due to the loss of muscle mass in elderly individuals, the effect of each exercise may be slightly worse than that of the young. However, the cumulative impact of longer exercise durations, such as more than 12 weeks, can probably compensate for this, resulting in a significant increase in CATB levels. The level of IL-6 increased after 12 weeks of exercise 3 times a week at any intensity but decreased after 12 weeks of exercise 5 times a week. The level of IL-6 increases due to the long-term contraction activity of skeletal muscle, which produces and releases IL-6. Training 5 times a week may exceed the appropriate amount of exercise for skeletal muscle. As a result, it causes damage and potentially local inflammation, depleting IL-6 and acting as an anti-inflammatory agent, thus inducing a decrease in the level of IL-6 [28, 35]. This indicated that the frequency of 5 times per week is too intense for elderly individuals, resulting in myokine depletion. AE can regulate the levels of myokines, such as BDNF, CATB, VEGF, and IL-6, to maintain and improve the function of the nervous system and blood vessel morphology, thereby delaying brain aging. In general, it may be possible to use a low- to moderate-intensity exercise prescription for 12 weeks or more, with a frequency of 3 times a week.

RE is also a practical exercise to delay aging. In addition to enhancing muscle strength, stimulating muscle hypertrophy, and delaying aging, it also has a good effect on promoting and improving cognitive function and brain memory [76‒78]. Studies have shown that RE can promote muscle protein synthesis, increase muscle mass in skeletal muscle, and avoid muscle atrophy by activating the mTORC1 signaling pathway [79]. At the same time, RE has a similar effect to AE, which can stimulate skeletal muscle to produce and release myokines to promote brain health. Five studies in this review involved changes in the levels of myokines by the intervention of RE. Currently, the most effective exercise prescription is 12 weeks, 2 or 3 times a week, at low or moderate intensity. The levels of the involved myokines, including BDNF, irisin, IGF-1, and CATB, are all increased, which may be attributed to the fact that as antagonistic exercise, RE requires a long duration of muscle force and continuous stimulation and may induce draft during training. However, [38] found no significant increase in BDNF after 22 weeks of low- to moderate-intensity exercise twice a week, while [80] found no significant increase in BDNF levels after 16 weeks of moderate-intensity RE twice a week. The difference may be related to participants’ willingness to take part in the exercise. The first two were performed in the laboratory environment using exercise equipment such as barbells and dumbbells. [35, 36] asked the participants to perform exercises that are easy to perform in their free time, which may make them have a solid willingness to exercise during the intervention. One study [81] found that BDNF increased in rats exposed to an environment with abundant opportunities for physical activity stimulating voluntary exercise and in rats subjected to combined AE and RE intervention. However, the increase was more pronounced in the former. [82], through two independent experiments of voluntary resistance running and normal running, also found that the BDNF signal level of rats with voluntary resistance running intervention was significantly higher than that of the normal running group. In the Morris water maze test, the former group had a shorter escape latency and path length, indicating better spatial learning and memory function. This change suggests that when conducting RE training in the elderly population, the form of exercise should be fully considered to mobilize the participation willingness of the elderly population. Nevertheless, its specific influence and effect need to be further explored.

In recent years, the use of combined exercise has gradually increased. Combined AE and RE allows people to perform both AE and RE in one session, which has a good effect on weight loss, fat loss, and muscle strength increase and is increasingly recognized by people. Studies have found that combined AE and RE can more effectively improve muscle protein synthesis, maintain muscle mass, and reduce the occurrence of sarcopenia due to anabolic resistance and impaired muscle mass [83]. At the same time, combined exercise may also play protective and nutritional roles in the brain through myokines released by skeletal muscle. However, there are still few studies on the effect of combined AE and RE on myokine levels from the perspective of muscle-brain crosstalk. Among the literature included in this review, there were only three studies on the level of myokines by the combined AE and RE intervention. The primary intensity was moderate or moderate to high, but the frequency and duration span choices were extensive. Moreover, the application of such exercise was mostly seen in related studies on BDNF expression. One study [75] found that after 12 weeks of daily moderate-intensity combined AE and RE training for obese SD rats injected with Aβ protein, the expression of peroxisome proliferator-activated receptor gamma coactivator-1α, FNDC5, and BDNF protein in the rats was activated, and the level of BDNF increased. Short-term memory and spatial perception abilities were improved in the passive avoidance test and Morris water maze test. The improvement in short-term memory was particularly significant. One study [84] found an increase in BDNF levels and an improvement in cognitive function in elderly females under a combined exercise intervention 3 times a week for 12 weeks. Combined AE and RE 3 or more times a week for 12 weeks seems to significantly regulate BDNF levels. However, another study [85] found that 16 weeks, 3 times a week, combined exercise intervention had no significant effect on BDNF levels. The study reached the conclusion that combined exercise for 16 weeks cannot effectively improve BDNF in diabetic patients with neuropathy. This result may be related to the nature of the disease. Many patients with diabetes have weaker body functions, and they also need BDNF to intervene in blood glucose regulation. Therefore, there was no significant improvement in BDNF levels. Hence, the exercise prescription of combined AE and RE remains to be studied, and its regulatory effect on the expression of other myokines still needs more empirical evidence.

In recent years, the application of mixed exercise, such as HIIT and HICT, has gradually increased and has been recognized and accepted by people for obtaining better results in a short time. Both HIIT and HICT can effectively increase muscle fiber recruitment, enhance skeletal muscle’s ability to regulate enzymes, and enhance muscle strength. At the same time, they are beneficial stimuli to improve glucose uptake and cognitive function, produce and release myokines such as VEGF, BDNF, and IL-6, and reduce inflammation while nourishing the brain [44]. However, only a few research experiments have been carried out on the influence of myokine levels from the perspective of muscle-brain crosstalk. Only one paper for each of the two types of exercise is included in this review. One study [43] found that 7 weeks of HIIT, with a frequency of 5 times a week, significantly increased VEGF levels, possibly due to the slight damage to skeletal muscle caused by HIIT. VEGF is released during the injury-repair process. Another study [44] found that HICT 3 times a week for 5 weeks increased BDNF and IL-6 levels. However, the improvement lasted only 24 h after the last training session. This may be because high-intensity exercise produces strong stimuli that cause skeletal muscles to respond more quickly. However, once the stimulation is gone, the response gradually wears off. Three times a week also gives skeletal muscles a buffer time so they do not tire out their response to stimuli and become unresponsive. In addition, significant improvements in cognitive function were found by the Stroop interference test, the Kosch block test, and the 2-min arithmetic interference test. Irisin, FGF-21, and CATB levels were associated with age. In older participants, irisin levels increased, while FGF-21 and CATB levels decreased. High-intensity cycling exercise stimulated skeletal muscle more than combined AE and RE, which may explain why BDNF levels continued to increase after short-term exercise. However, [86] found that after a single session of high-intensity cycling, BDNF levels decreased 1 h later and reversed 24 h later. After the same cognitive test, cognitive function decreased in the older participants. This may be due to older participants needing help to adapt to the type and intensity of exercise. As a result, cognitive ability was not fully recovered by the time cognitive function was tested. HIIT and HICT are mixed exercises with certain risks, especially when applied to the elderly population. Consequently, their application in the elderly population also has certain limitations. It is necessary to pay close attention to the physical condition of the elderly to avoid injury.

The type, duration, intensity, and frequency of exercise may affect the expression of myokines and their roles in muscle-brain crosstalk. Different myokines may have their own sensitive exercise type, duration, frequency, and intensity, while these myokines enter the circulation with the blood, directly or indirectly playing the role of nutrition and protection of the brain, promoting brain function, making the brain act on the muscles to better control and regulate muscle nutrition and blood supply, and promoting the function of skeletal muscle. The two promote each other to maintain muscle-brain health. AE and RE are widely used at present. Both low- to moderate-intensity AE 3 times a week for 12 weeks or more and RE 2 or 3 times a week at low to moderate intensity for 12 weeks have a good effect on the expression of myokines. However, the specific exercise prescription of combined AE and RE, HIIT, and HICT cannot be determined because of the paucity of studies. More empirical studies are needed in the future. Considering the safety issues in the elderly population, HIIT and HICT are not recommended as the preferred exercise methods. In terms of AE and RE, AE, mainly as a whole-body exercise, can make the expression of myokines against RE more extensive. It is also more favored by the elderly population. This preference makes them more willing to perform AE independently. The expression of myokines may be more significant.

Consequently, to exert the beneficial influence of the expression of myokines regulated by exercise on chronic diseases in the elderly through muscle-brain crosstalk, it is more appropriate for the elderly population to adopt the exercise prescription of low- to moderate-intensity AE 3 times a week for 12 weeks or more. Exercise prescriptions for low- or moderate-intensity RE 2 to 3 times per week for 12 weeks can also be adopted if available, and the elderly are willing.

Some pictures in Figures 3, 4 were from scidraw.io drawn by Macauley Smith Breault.

The authors declare that they have no conflict of interest in this paper.

This work received no external funding.

All the authors contributed to the completion of this paper. C.W. and A.L. proposed the thesis theme; B.W., J.L., and C.W. collected literature and wrote the paper; B.W., C.W., and A.L. completed the editing and modification; B.W., J.L., and C.L. prepared the figures and table.

Bingqing Wang and Jiling Liang contributed equally to this work.