Combined Exercise and Vitamin D on Brain-Derived Neurotrophic Factor

Abstract

Brain-derived neurotrophic factor (BDNF) is a highly conserved neurotrophic protein of the nerve growth factor family. Neurotrophins are proteins that help to stimulate and control neurogenesis, BDNF being the most active one. BDNF may be useful in the prevention and management of several diseases including Multiple Sclerosis (MS) and Diabetes. Lifestyle modifications (physical activity and diet) are among the most promising strategies for altering BDNF levels. In this chapter, we aimed to investigate the effects of aerobic and resistance training and combined exercise and vitamin D therapy on BDNF levels.

1. Introduction

Brain-derived neurotrophic factor (BDNF) is a protein that belongs to the nerve growth factor (NGF) family and has been conserved throughout evolution. It plays a significant role in regulating synapses, affecting both their structure and function in multiple areas of the brain. BDNF also helps promote neuron survival, neuroplasticity, neurite growth, and synaptogenesis. BDNF is an important factor affecting cognitive function which has recently interested a bulk trend of effort in the health context [1, 2, 3]. BDNF was first isolated from the pig brain in 1982 by Yves-Alain Barde and Hans Thoenen [4] which was then cloned in 1989 [5]. BDNF is one of the neurotrophic factors that support differentiation. BDNF is a protein that, in humans, is encoded by the BDNF gene [6]. BDNF is one of the neurotrophic factors that support the differentiation, maturation, and survival of neurons in the nervous system and shows a neuroprotective effect under adverse conditions, such as glutamatergic stimulation, cerebral ischemia, hypoglycemia, and neurotoxicity [7, 8, 9]. BDNF is a member of the neurotrophins family of growth factors, which are related to the canonical NGF, a family which also includes NT-3 and NT-4/NT-5. It is widely expressed in the CNS [10], retina, kidneys, prostate, motor neurons, and skeletal muscle and is also found in saliva (31). BDNF binds to its high-affinity cell surface receptors, tyrosine kinase B (TrkB), and activates signal transduction cascades (IRS1/2, PI3K, Akt) [11], crucial for CREB and CBP production, that encode proteins involved in β-cell survival [12]. TrkB are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains [13]. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode TrkB [14]. TrkB has a crucial function in both regular cell processes and the advancement of various cancer types [15]. According to research, mutations in TrkB result in the activation of signaling pathways that influence protein expression [16]. BDNF and insulin-like growth factor-1 have similar downstream signaling mechanisms incorporating both p-CAMK and MAPK that increase the expression of pro-survival genes [17]. BDNF protein and mRNA have been identified in most brain areas including the olfactory bulb, cortex, hippocampus, basal forebrain, mesencephalon, hypothalamus, brainstem, and spinal cord [17, 18] which stimulates and controls neurogenesis which is the growth of new neurons from neural stem cells [19]. Decreased levels of BDNF are associated with neurodegenerative diseases with neuronal loss, such as Parkinson’s disease (15), Alzheimer’s disease (27), Multiple Sclerosis (MS) (16), and Huntington’s disease (17). Besides the neuroprotective effect, BDNF plays a major role in energy homeostasis. The peripheral or intracerebroventricular (ICV) BDNF administration suppresses energy intake and reduces body weight [20]. BDNF has been identified as a key component of the hypothalamic signaling pathway. This explains why BDNF controls body weight, decreases food intake, lowers blood glucose levels and controls energy homeostasis [20].

BDNF plays an important role in neuronal survival and growth, serves as a neurotransmitter modulator, and participates in neuronal plasticity, which is essential for learning and memory [21]. BDNF is responsible for making your neurons stronger. Nevertheless, BDNF isoforms have also been observed to affect neuronal activity by being associated with cellular models of memory (i.e., long-term potentiation and long-term depression) [22]. Neurotrophic factors regulate neuronal differentiation, phenotype maintenance, and synaptic sprouting [23]. They also protect adult neurons from mechanical, toxic, or ischemic injuries and interfere with the death of neurons by necrosis or apoptosis [24]. Lifestyle modifications (physical activity and diet) are among the most promising strategies for altering BDNF levels. We aimed to investigate the effects of aerobic and resistance training and combined exercise and vitamin D therapy on BDNF levels.

2. Function of brain-derived neurotrophic factor (BDNF)

BDNF may be useful in the prevention and management of several diseases including MS and Diabetes [25, 26]. In the brain, it is active in the hippocampus, cortex, and basal forebrain areas vital to learning, memory, and higher thinking [27]. Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells in a process known as neurogenesis. BDNF acts on certain neurons of the central nervous system and the peripheral nervous system expressing TrkB, helping to support the survival of existing neurons, and encouraging growth and differentiation of new neurons and synapses [28]. Neurotrophins are proteins that help to stimulate and control neurogenesis, BDNF being one of the most active ones [29]. Endogenous BDNF is known to be involved in cellular development and growth, mood regulation, and cognitive functions such as learning and memory. BDNF appears to be a crucial regulatory mechanism in the growth and development of neurons across various regions of the brain. It has also been shown to enhance neuron survival by increasing resistance to nerve damage [30]. Mice born without the ability to make BDNF have developmental defects in the brain and sensory nervous system, and usually die soon after birth suggesting that BDNF plays an important role in normal neural development. BDNF also regulates both excitatory and inhibitory synaptic transmission and activity-dependent plasticity as a key molecule involved in plastic changes related to learning and memory [31]. Emerging data indicate that the induction of localized axonal synthesis by BDNF underlies its role in regulating synaptic efficacy. Changes in BDNF expression are associated with both normal and pathological aging and also psychiatric disease, in particular in structures important for memory processes such as the hippocampus and para-hippocampal areas; as a results, BDNF itself is important for long-term memory [32]. BDNF has a role in axonal guidance and regulates activity-dependent synaptic plasticity and long-term potentiation [33]. Neurotrophins are essential for short-term neuronal plasticity and long-term neuroprotection in the CNS. The survival and morphogenesis of CNS neurons depend on BDNF/TrkB-stimulated signaling. Activation of different intracellular signaling pathways, including MAPK/ERK, PLCγ, and PI3K, is triggered when BDNF binds to TrkB. These mechanisms are responsible for the biological effects that BDNF has on neurons [34]. BDNF/TrkB-stimulated intracellular signaling is critical for neuronal survival, morphogenesis, and plasticity [35]. BDNF regulates glucose and energy metabolism and prevents the exhaustion of β cells [36]. Findings also indicate that BDNF is involved in both central metabolic pathways and the mediation of energy metabolism in peripheral organs. Recent findings suggest that the BDNF signaling pathway in the hypothalamus may have the ability to regulate energy balance, control body weight, and influence feeding behavior [37]. BDNF is a protein produced by muscle cells during exercise that can enhance the breakdown of fat in skeletal muscles through a process dependent on AMP-activated protein kinase [38].

3. The effect of aerobic exercise on the brain-derived neurotrophic factor (BDNF)

Low circulating BDNF levels have been associated with a wide range of neuropsychiatric disorders including depression, schizophrenia, and neurodegenerative diseases, although no causal relationship has yet been established [39, 40]. Over the last 10 years, studies have examined what causes short-term and long-term increases in BDNF levels in animal brains and human blood. These studies assume that higher levels of BDNF can benefit brain health [41]. Certain types of physical exercise have been shown to markedly (threefold) increase BDNF synthesis in the human brain, a phenomenon that is partly responsible for exercise-induced neurogenesis and improvements in cognitive function [42]. The release of BNDF in humans is stimulated by physical activity and may be related to improvements in executive function [43]. Executive function is responsible for higher cognitive processes involved in managing other basic cognitive functions. Aerobic exercise is proposed to induce the expression of BDNF throughout the central nervous system, which in turn, can enhance synaptic plasticity (52). Research has consistently shown that aerobic exercise can elevate baseline BDNF levels in the hippocampus, striatum, and various cortical regions in laboratory animals [44]. Encouragingly, BDNF transcription can be induced in the rat hippocampus after only three consecutive days of aerobic exercise [45]. Exercise promotes the expression of BDNF through the action of the ketone body β-hydroxybutyrate [46]. A form of physical activity known as aerobic exercise has been proven to have positive effects on individuals with neurological disorders who undergo this type of training [47]. For example, after a program of aerobic exercise, individuals with stroke [48], MS (16), and Parkinson’s disease (15) have shown improvements in walking, functional ability, and motor performance. In addition to gains in cardiorespiratory fitness, exercise-induced increases in BDNF levels in the motor cortex and hippocampus have also been associated with enhanced learning and memory [49]. Additionally, it guides decision-making processes for motor tasks and healthy behaviors. It has been suggested that this increase in BDNF is associated with enhanced hippocampal synaptic plasticity, which supposedly enhances synaptic transmission and increases the expression of molecules associated with learning and memory [50]. Recent research indicates that the levels of BDNF, which increase after short-term exercise, can continue to rise with long-term aerobic exercise [51]. Long-term endurance training in humans has been shown to result in an increase in resting serum BDNF levels that persist over time [52]. In contrast, some studies have reported that the duration of aerobic exercise does not have a significant influence on resting levels of serum BDNF [51, 53]. Several mechanisms have been proposed to explain the positive impacts of aerobic exercise. These include increased cerebral blood flow, changes in neurotransmitter release, structural changes in the central nervous system, and altered arousal levels [54]. Serotonin levels regulate BDNF, which is a potential cause of serotonin-delivering axon growth. Similar to exercise, antidepressants increase BDNF levels, which could explain their effectiveness in improving mood [55]. A recent review and meta-analysis of 29 studies investigating the effect of exercise on BDNF in healthy humans found that a single session of aerobic exercise significantly increases BDNF levels immediately post-exercise demonstrating a moderate effect [56]. Furthermore, in the same review, a program of aerobic training was shown to significantly increase resting levels of BDNF, with a small effect size [56]. These findings provide evidence that both single and long-term aerobic exercise has a significant impact on BDNF levels in healthy humans.

Aerobic training has been shown to improve brain function, and one of the mechanisms behind this effect is thought to be an increase in BDNF [57]. BDNF is a protein that promotes the growth and survival of neurons in the brain, and it plays a key role in learning, memory, and cognitive function [58]. Studies have found that aerobic exercise can increase levels of BDNF in both animals and humans [59]. This may be because exercise stimulates the release of various growth factors, including BDNF [60]. In addition, exercise has been shown to increase blood flow to the brain, which may also contribute to the increase in BDNF levels [60]. Once released into the brain, BDNF binds to specific receptors on neurons and triggers a cascade of molecular events that promote neuron survival and growth. These events include the activation of various signaling pathways, such as the MAPK/ERK pathway, which leads to increased protein synthesis and enhanced neuronal plasticity. Overall, these cellular and molecular mechanisms suggest that aerobic exercise can have a powerful impact on brain function by increasing levels of BDNF [61]. By promoting neuron survival and growth, BDNF may help support cognitive function and protect against age-related decline [62].

4. The effect of resistance exercise on the brain-derived neurotrophic factor (BDNF)

Strength training is a staple for physical and mental health. The benefits are not only stronger bones, ligaments, tendons, and muscle tissues but also a more capable mind [63]. Recently studies demonstrated that resistance exercise can also elevate BDNF levels in the hippocampus (50). Exercise has been proven to promote neurogenesis by increasing BDNF and lowering cortisol [64]. The exact process and mechanism by which resistance exercise increases BDNF, leading to changes in neuroplasticity, is not yet fully understood (41). There were contradictory results in the literature regarding the response of BDNF to resistance training some found positive BDNF response while some reported no differences between BDNF levels before and after training. Lodo et al. investigated the response of neurotrophic factors in schemes of equal volume consisting of two resistance training sessions with 1 week of rest between the sessions with a total of 30 participants suggesting that the intensity of resistance training is not a significant factor in the neurotrophic factor response when the total load lifted is equated in the range of submaximal repetition [65]. Another study investigated the effect of a resistance exercise 3×/week for 6 weeks in two groups of 80% one repetition maximum (1RM) with low repetition and 65% 1RM with high repetition in men with at least 2 years of resistance training experience hypothesizing that a minimum volume and greater proximity to one repetition maximum may be required to elicit a BDNF response [66].

Additionally, studies investigated the effect of short and longer training sessions, only two or three compared to 15–40 sessions, showing significant differences concerning BDNF between these studies, but it is not possible to conclude which (single sessions vs. several sessions) may produce a better BDNF response. The available research on BDNF and its relationship with resistance and strength training yields inconclusive results. From the studies conducted, it appears that high-intensity workouts at 70% or above based on 1RM, low repetition, and specific rest periods are necessary to induce changes in BDNF levels. Additionally, whole-body training or lower-body training with free weights and multi-joint movements may produce more favorable outcomes [67]. Further studies are needed to draw a better conclusion for BDNF response to resistance training.

Resistance training has been shown to have a significant impact on BDNF [68]. This protein is responsible for the growth and survival of neurons in the brain, as well as synaptic plasticity [69]. Resistance training stimulates the production of BDNF through a variety of cellular and molecular mechanisms [70]. One mechanism by which resistance training increases BDNF levels is through the activation of the mTOR pathway. This pathway plays a critical role in regulating protein synthesis and cell growth and has been linked to increased BDNF expression [70]. In addition, resistance training has been shown to increase the activity of AMPK, an enzyme that regulates energy metabolism and promotes mitochondrial biogenesis. This process may also contribute to the upregulation of BDNF. Another cellular mechanism by which resistance training affects BDNF is through modulation of oxidative stress [71]. Exercise-induced oxidative stress can stimulate the expression of antioxidant enzymes, which protect against damage caused by free radicals. These enzymes may also indirectly increase BDNF levels by reducing inflammation and improving overall neuronal health. Finally, resistance training may promote BDNF expression through its effects on neurotransmitter systems [72]. Exercise has been shown to increase dopamine and serotonin release in the brain, both of which are known to stimulate BDNF production. Additionally, exercise-induced changes in glutamate receptor activity may also contribute to increased BDNF expression [73]. In conclusion, resistance training has a profound impact on BDNF levels through a complex interplay of cellular and molecular mechanisms. By promoting the growth and survival of neurons in the brain, resistance training has the potential to enhance cognitive function and improve overall neurological health.

5. The effect of vitamin D on brain-derived neurotrophic factor (BDNF)

Vitamin D is a steroid hormone essential for maintaining calcium metabolism and various extra-skeletal functions. Noteworthy, vitamin D controls more than 1000 genes, including those responsible for the regulation of cellular proliferation, differentiation, apoptosis, and angiogenesis [74]. This steroid hormone plays an important role in the nervous system, including differentiation, calcium regulation, homeostasis, modulation, the release of neurotrophins, and the activity of brain genes and neurotransmitter metabolism enzymes [75, 76]. As a result of restricted sunlight exposure and/or dietary intake, many people are vitamin D deficient and need vitamin D supplements to meet their vitamin D requirement. Very frequently vitamin D insufficiency can occur with several potential consequences, many of which are still under investigation. Vitamin D supplementation acts to improve performance speed and proximal muscle strength, thus reducing the risk of falls, osteoporosis, and fractures in post-menopausal women [77]. In addition to its well-established action in calcium homeostasis, vitamin D is being reconsidered as a neuroprotective steroid. The reported neuroprotective effects of vitamin D include the in vitro biosynthesis of neurotrophic factors, the inhibition of nitric oxide synthase, and the increased glutathione levels in the brain detoxification pathways [75]. Vitamin D is potent in vitro inducer of NGF mRNA expression in neural brain cells and protects the brain cortex against amyloid-beta-induced toxicity. While, suppression of vitamin D receptor (VDR) in neuronal cultures disrupts L-type voltage-sensitive calcium channels and NGF production, increasing vulnerability to aging and neurodegeneration. Vitamin D and its analogs can cross the blood-brain barrier, and it has been shown that VDR and enzymes involved in the bioactivation and catabolism of vitamin D are abundantly expressed in the brain neural cells, particularly in areas affected by neurodegenerative disorders [23]. Indeed, vitamin D stimulates the expression of P75NTR, the neurotrophins low-affinity receptor. Vitamin D supplementation plays a crucial role in the modulation of neurotrophic factors that may reflect a compensatory mechanism. Confirming animal studies, low levels of circulating vitamin D may cause cognitive decline not affected by neurological impairment in human subjects and this can be reversed by vitamin D substitution therapy [78]. It must be taken into account that postmenopausal women or MS patients, as well as amenorrhoeic subjects, showed lower plasma BDNF levels. Vitamin D and some metabolically active precursors modulate the synthesis of neurotrophins, thus, neurons could therefore be vulnerable to aging and neurodegeneration when there is a long-term or permanent deficiency [79]. Vitamin D’s significance in calcium metabolism and neurotrophic factors regulation is crucial to the brain’s functioning, as well as BDNF’s role in supporting neuron survival. Further research should investigate how vitamin D impacts BDNF-related health outcomes.

One proposed mechanism by which vitamin D may affect BDNF is through its ability to regulate gene expression. Vitamin D receptors are found throughout the body, including in the brain, where they can bind to specific DNA sequences and influence the expression of genes involved in neuroplasticity and cognition [80]. In addition to its effects on gene expression, vitamin D may also modulate BDNF levels through its anti-inflammatory properties [80]. Chronic inflammation has been linked to decreased BDNF levels, and studies have shown that vitamin D can reduce inflammation in both the peripheral and central nervous systems [81]. Finally, research has suggested that vitamin D may interact with other molecules implicated in BDNF regulation, such as serotonin and dopamine. These neurotransmitters play important roles in mood regulation and cognitive function, and their interaction with vitamin D may provide further insight into the mechanisms underlying the relationship between vitamin D and BDNF.

6. The effect of combined exercise & vitamin D on the brain-derived neurotrophic factor (BDNF)

The evidence on the interactive effects of exercise and vitamin D supplementation on neurotrophic factors and neuronal growth is limited and controversial. Exercise has been reported to exert neuroprotection by neurogenesis and angiogenesis. On the one hand, exercise increases growth factor signaling by reducing inflammatory factors and improving growth factor levels [82]. On the other hand, one of the non-invasive treatment approaches proposed in diseases is the use of vitamin D. The findings show the superiority of using combined exercise and vitamin D strategy over exercise or vitamin D alone in increasing BDNF [83]. In addition, the antioxidant effects of vitamin D supplementation and exercise have a positive role in the regulation of neurotrophic factors and growth cells of the nervous system, as well as the function of immune system regulatory cells, due to their direct effect on the secretion of stress-related hormones, including glucocorticoids by reducing the level of oxidative stress and inflammation. In this regard, Horn et al. reported that the increase in BDNF expression following exercise is regulated by neurotransmitters (glutamate, acetylcholine, and serotonin) and GABA receptors and environmental hormones (estrogen, progesterone, and testosterone, growth, and glucocorticoid) [84]. Also, Bahmani et al. reported that combined aerobic training and vitamin D supplementation increased BDNF and NGF, and downregulated CRP, TNF-a, IL-6, and IL-1β more effectively than either alone in MS patients suggesting combined therapy as a better approach to improve neurotrophins and inflammatory biomarker levels in female MS patients [85]. Babaei et al. studied the beneficial effects of aerobic exercise on metabolic syndrome components, cognitive performance, BDNF, and irisin in ovariectomized rats with different serum vitamin D levels reporting that vitamin D insufficiency deteriorates metabolic syndrome components and elevates serum BDNF as a compensatory metabotropic factor, and further high dose of vitamin D supplementation along with aerobic exercise significantly attenuates these components parallel with a reduction in BDNF [86]. Also, another study investigated the effect of aerobic training and vitamin D supplementation on fatigue and quality of life in patients with MS during the COVID-19 outbreak that showed aerobic training and vitamin D supplementation effectively reduced fatigue and improved the QoL in female MS patients in favor of combined protocols than separate protocols [86].

Physical exercise and vitamin D have both been linked to increased levels of BDNF, a protein that plays an important role in the growth and survival of neurons [87]. Research has shown that combining exercise with vitamin D supplementation can lead to even greater increases in BDNF levels. One possible mechanism for this effect is through the regulation of gene expression [88]. Exercise and vitamin D have both been shown to regulate the expression of genes related to BDNF, leading to increased production of the protein. Another possible mechanism is through the modulation of inflammation. Both exercise and vitamin D have anti-inflammatory effects, and chronic inflammation has been linked to decreased BDNF levels. By reducing inflammation, exercise and vitamin D may help to increase BDNF production [89]. Exercise also increases blood flow to the brain, which may contribute to the increase in BDNF levels seen with combined exercise and vitamin D supplementation. This increased blood flow may also improve oxygen delivery to neurons, further supporting their survival and growth [90]. Vitamin D has also been shown to play a role in calcium signaling within neurons, which is important for their function and survival [91]. Combined with exercise-induced increases in calcium signaling, this may lead to greater BDNF production. Finally, both exercise and vitamin D have been linked to improvements in mood and cognitive function. These improvements may be mediated by increased BDNF levels, as the protein is known to promote neuronal plasticity and support learning and memory processes [90]. In conclusion, several cellular and molecular mechanisms may explain the beneficial effects of combined exercise and vitamin D on BDNF levels. These mechanisms include regulation of gene expression, reduction of inflammation, increased blood flow to the brain, modulation of calcium signaling, and improvements in mood and cognitive function. Further research is needed to fully understand these mechanisms and how they contribute to overall brain health (Figure 1).

Figure 1.

The combined effect of exercise and vitamin D on BDNF.

7. Conclusions

In conclusion, the combination of exercise and vitamin D has been shown to have a positive effect on BDNF levels. Studies suggest that regular physical activity can increase BDNF levels, while vitamin D supplementation may enhance the effects of exercise on BDNF. These findings have important implications for individuals looking to improve their cognitive function and overall brain health. Incorporating both exercise and sufficient vitamin D intake into one’s lifestyle may provide a simple yet effective way to support healthy brain function throughout life. However, more research is needed to fully understand the mechanisms behind these effects and how they vary in different populations.

Conflict of interest

No potential conflict of interest was reported by the authors.