Impact of High-Intensity Exercise on BDNF Levels and Its Implications in High-Performance Sport: A Systematic Review

Abstract

The brain-derived neurotrophic factor (BDNF) is a crucial protein in the development of the cognitive system. It regulates the growth of neurons and glial cells, synaptic plasticity, and neuroprotection. Background/Objectives: It has been suggested that high-intensity exercise could modulate the mechanisms of BDNF release, with potentially significant implications in the professional sports world. However, this is not yet fully proven, and the underlying physiological alterations are unknown. Methods: This paper reviews the current scientific literature to clarify the uncertainties about how high-intensity physical exercise influences BDNF release and its relationship with high-performance sports. Results: Strenuous exercise appears to increase BDNF synthesis through the action of lactate and the PGC-1α/FNDC5 pathway. Additionally, cognitive function has been described as an element to consider for maximizing sports performance. Conclusions: In this regard, this review provides a solid starting point for further investigation into the molecular mechanisms that promote BDNF expression mediated by exercise, as well as for seeking a direct correlation between the role of cognitive development and athletic performance in high-performance athletes.

1. Introduction

The first scientific evidence reporting a significant improvement in mental health due to physical exercise dates back to the 1980s [1]. Physical activity was presented as a means to reduce symptoms of various mental disorders, such as anxiety and depression. Today, advancements in research methods have allowed for deeper insights and the refinement of results concerning the influence of exercise on brain function. The are numerous biomarkers that have been described over previous decades as reliable indicators to assess the benefits of exercise on brain activity.

In 1978, a study analyzed brain growth-promoting activity [2]. In this research, a protein involved in neuronal development, the brain-derived neurotrophic factor (BDNF), was mentioned for the first time. It is a neurotrophin that participates in and regulates numerous mechanisms related to the development and maintenance of brain function [3]. This protein is encoded by the BDNF gene.

The genetic variability of BDNF underpins the broad functional spectrum of the protein. Additionally, during the synthesis process, intermediate isoforms with biological activity are generated, binding to different receptors and enhancing multiple signaling pathways. Initially, pre-proBDNF, a precursor, is synthesized in the endoplasmic reticulum and then travels to the Golgi apparatus, where its pre-region is cleaved to form proBDNF. This proBDNF matures into mBDNF through the action of endoproteases around the Golgi apparatus or within intracellular vesicles via convertase enzymes [4]. proBDNF and mBDNF serve different functions, as they bind to distinct neuronal receptors. mBDNF binds to the tyrosine kinase Trk receptors (TrkB) on the membrane, while proBDNF binds to the p75 neurotrophin receptor (p75NTR).

In general, BDNF is involved in controlling the development of neurons and glial cells, as well as in modulating short- and long-term synaptic interactions. Its neuroprotective role and involvement in synaptic plasticity are particularly noteworthy [5]. The activation of p75NTR by proBDNF leads to the formation of various intramembrane complexes. Primarily, three signaling pathways are deployed, mediated by three molecules: c-Jun N-terminal kinase (JNK), Ras homolog family member A (RhoA), and nuclear factor kappa B (NF-kB). The JNK-related pathway triggers programmed cell death, the RhoA-mediated pathway regulates the development of the neuronal growth cone, and finally, NF-kB promotes neuron maintenance and survival [5].

On the other hand, the binding of mBDNF to the TrkB receptor causes it to dimerize and undergo autophosphorylation. This activates the transcription factor CREB and initiates four signaling cascades mediated by various enzymes such as phosphatidylinositol-3-kinase (PI3K), MAP kinase (MAPK), phospholipase C gamma (PLC-γ), or certain GTPases [5]. The PI3K pathway modulates synaptic plasticity and enhances dendritic growth and branching; the MAPK pathway regulates protein synthesis during neuronal differentiation; the PLC-γ-mediated pathway is also involved in synaptic plasticity, while the GTPase complexes stimulate the development of neuronal fibers.

Regarding synaptic plasticity, it is the nervous system’s ability to modify its morphology based on incoming and outgoing stimuli throughout development. Several mechanisms of plasticity have been described, with long-term potentiation (LTP) standing out. LTP is a change in synaptic morphology that lasts for hours or even days and is deeply related to memory and learning. BDNF has been shown to play an important role in regulation through its signaling cascades, as they promote the transcription of genes involved in synaptic modulation and participate in various cognitive processes [6].

Over the past decade, multiple studies have sought to describe the mechanisms of BDNF release and the factors that could modify it. It has been shown that BDNF is not only released in the brain. The lungs, intestines, and skeletal and cardiac muscles are some of the tissues that secrete BDNF into the bloodstream [7]. Specifically, vascular endothelial cells are one of the main sources of BDNF secretion. Additionally, BDNF synthesis was found to be modified under conditions of physiological stress. For example, an increase in body temperature in response to physical exercise has been linked to a rise in BDNF levels. It has been demonstrated that vascular endothelium releases BDNF due to shear stress in vitro, and it has been suggested that the presence of the TrkB receptor in these cells may form part of a positive feedback loop with circulating BDNF [8]. Coupled with the fact that skeletal muscle tissue serves as a source of BDNF, this led to the hypothesis that physical exercise could play a key role in its release [7]. The physiological stress generated after high-intensity exercise leads to an increase in lactate release into the blood, as well as a rise in energy demands and changes in the levels of energy molecules such as ATP and NADH. There are molecules like sirtuins whose activity is affected by the levels of these energy molecules [9]. Additionally, certain hormones are also affected after intense exercise. Irisin is a peptide hormone derived from the FNDC5 gene and is secreted by skeletal muscle cells. It regulates numerous beneficial effects of exercise on the body [10].

In light of the above, the aim of this work is to review the existing scientific literature from 2020 to the present, synthesizing the results obtained from studies assessing the link between physical exercise and BDNF release in humans. Additionally, an attempt will be made to explore a possible correlation between the conclusions drawn and how they could impact the world of professional sports.

2. Study Determination

In this review, multiple scientific articles that study the effect of high-intensity exercise on the release of BDNF in humans were selected and examined, based on principles of transparency and traceability, using reliable sources and specific, well-defined inclusion and exclusion criteria. In this regard, the study has been conducted following the PRISMA guidelines (an acronym for “Preferred Reporting Items for Systematic Reviews and Meta-Analyses”) [11].

A standardized search was conducted in April 2024 across the following databases: Web of Science, SCOPUS, and PubMed. Both original articles and general reviews addressing the influence of physical exercise on BDNF release were included. Keywords such as “BDNF” (MeSH ID: D019208), “release”, “physical exercise”, and “training” were used, along with Boolean operators like AND and OR.

Initially, the selection was based on the PICO criteria: studies in humans [P] exposed to high-intensity physical exercise [I] compared to groups not performing any exercise [C] to determine the resulting alteration in BDNF release [O]. The final articles included in the review were selected according to the following inclusion and exclusion criteria (

Table 1. Inclusion and exclusion criteria used in the study selection.

Inclusion and Exclusion Criteria
Inclusion criteria	Exclusion criteria
- Articles studying the influence of high-intensity physical exercise on BDNF release in humans - Written in English or Spanish - Full-text articles - Original studies - Any sex - Young age - Studies published after 2020	- Articles studying BDNF release in patients with diseases - Animal studies - Studies published before 2020 - Trials involving older adults - Studies focusing on BDNF polymorphisms - Duplicate articles - Reviews - Incomplete articles - Articles not addressing the research question

):

To conduct a rigorous and transparent review, the PRISMA diagram was used. This tool allows for the visualization of the study selection process, providing clarity regarding the decisions made at each stage (Figure 1). Moreover, this review adheres strictly to the PRISMA guidelines to ensure methodological rigor and transparency. By following PRISMA standards, we have systematically selected, evaluated, and synthesized the most relevant studies, thereby enhancing the reliability and reproducibility of our findings.

3. Results

3.1. Introduction to Analysis of Studies

Seven scientific articles investigating the impact of moderate-to-high-intensity physical exercise on BDNF release have been reviewed. The selected studies followed different physical activity protocols and measured BDNF levels before and after training (

Table 2. The results of the reviewed studies. Abbreviations: HIIT (High-Intensity Interval Training), GTX (Graded Exercise Test), MICT (Moderate-Intensity Continuous Training), VICT (Vigorous-Intensity Continuous Training), SIT (Sprint Interval Training).

Description of the Included Studies
Studies	Study Design	Population Gender	Population Status	No. Population	Population Age	Type of Exercise	Duration	Exercise Intensity	BDNF Increase Compared to Control
[12]	Cross-over	Male	Regular exercise	20	$\overline{\mathrm{x}}$ = 23.03	Cycling	30 min/15 min	Moderate/acute	Yes
[13]	Cross-over	Male	Untrained students	12	$\overline{\mathrm{x}}$ = 23.7	Cycling/HIIT	35 min per test	Acute	Yes
[14]	Parallel	Female	Young sedentary	17	N/A	HIIT/GTX	3 sessions × 4 weeks 17.5 min (3 sessions) 22 min (3 sessions) 26.5 min (6 sessions)	Acute	Yes
[15]	Cross-over	Male	Active	8	$\overline{\mathrm{x}}$ = 23.1	Running (MICT, VICT, and SIT)	3 h per session	Moderate/acute	Yes
[16]	Cross-over	Male and female	3 months resistance training	30 (15 and 15)	$\overline{\mathrm{x}}$ = 22	Bench press/squat	4 × 10 (35% 1RM) 4 × 5 (70% 1RM)	Moderate/acute	Yes
[17]	Cross-over	Female	Athletes	17	$\overline{\mathrm{x}}$ = 20.0	GXT/HIIT	12 min per session	Acute	No
[18]	Parallel	Male and female	Athletes Regular fitness Sedentary	20 (11 and 9) 19 (9 and 10) 23 (10 and 13)	$\overline{\mathrm{x}}$ = 20.2	N/A	30 min	Acute/moderate	Yes

). A total of 166 participants made up the sample, 85 of whom were men (51.20%), and the remaining 81 were women (48.8%). Only 20 athletes participated in the studies, while 77 individuals were regularly and actively involved in sports, with 30 specifically engaged in endurance sports. There were 69 sedentary participants, all of whom were apparently healthy.

3.2. Comparative Analysis and Key Results

The reviewed articles showed differences in the protocols used to stimulate BDNF release in the body, yet the results seem to converge in most cases.

Ref. [12] revealed that moderate and high-intensity exercise tests can induce an increase in BDNF due to their contribution to neurogenesis and synaptic plasticity. They also conducted associative memory tests, where the population subjected to moderate exercise showed better results. However, high-intensity exercises did not lead to significant improvements in the analyses or memory tests.

Ref. [13] reported positive results regarding BDNF levels following high-intensity exercise sessions. Additionally, they suggested that lactate generated during exercise might be a possible molecular mechanism involved in increasing BDNF.

Ref. [14] indicated that short-term HIIT programs (alternate short bursts of intense exercise with rest or low-intensity periods) increase circulating BDNF concentrations due to an increase in its brain synthesis. However, these levels were reduced after GXT sessions (tests where exercise intensity is progressively increased until exhaustion). Ref. [15] also employed HIIT and GXT protocols. In this case, the authors did not find that acute high-intensity exercise increased circulating BDNF levels.

Ref. [16] opted for strength training to assess changes in BDNF release. Their conclusions differed from those previously discussed. In this instance, the authors concluded that BDNF levels could increase after exercise, but the increase varied depending on factors such as body weight and training volume. They suggest that exercise intensity did not influence the neurotrophic factor response when training volumes were balanced.

Ref. [17] presented a trial where running tests at different intensities were performed to evaluate their impact on circulating BDNF levels. According to the authors, sprint interval training (SIT, interval training that involves very short bursts of all-out sprints followed by longer recovery periods) caused the highest increase in BDNF, followed by vigorous-intensity continuous training (VICT, continuous exercise with varying intensity levels throughout the session), and finally moderate-intensity continuous training (MICT, sustained exercise at a moderate intensity without significant fluctuations).

Lastly, Ref. [18] conducted a protocol that did not specify the type of exercise performed but did indicate the intensity (acute-moderate). The authors highlighted the increase in serum BDNF levels after the training session.

3.3. Lactate and Physiological Stress

Refs. [13,15,17] include lactate in their studies as one of the first responses to the question regarding the molecular mechanisms underlying the increase in BDNF levels following a high-intensity training session. According to these authors, physical exercise appeared to induce BDNF release via mechanisms such as the PGC-1α/FNDC5 pathway [13]. PGC-1α is the peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and FNDC5 is fibronectin type III domain-containing protein 5, identified as a precursor of the hormone irisin [17]. Lactate generated during exercise can cross the blood–brain barrier and activate the PGC-1α/FNDC5 pathway through SIRT1. Specifically, lactate elevates intraneuronal NAD⁺ levels, activating SIRT1 and the PGC-1α pathway. This activation promotes the expression of FNDC5/irisin, which, in turn, induces BDNF release [17].

However, the physiological stress induced by high-intensity exercise can act as a negative regulator of BDNF expression by interfering with lactate’s action [15]. Ref. [12] also noted in their study that high-intensity exercise did not result in an increase in BDNF levels. According to [15], cortisol released in response to this physiological stress seemed to prevent lactate from triggering the PGC-1α/FNDC5 pathway, thereby indirectly inhibiting BDNF synthesis. However, the authors did not precisely describe the molecular mechanisms accompanying these results.

4. Discussion

4.1. Exercise, BDNF, and Cognitive Development

This paper reviewed seven studies that mostly concluded that high-intensity exercise promotes the release of BDNF in humans. Some data suggested that moderate-intensity exercise also leads to an increase in BDNF synthesis [12]. However, other trials comparing acute and moderate-intensity exercises indicated that moderate-intensity exercise did not significantly increase BDNF release.

Similarly, there was no consensus on the role of physiological stress in high-intensity exercise and BDNF release. Nevertheless, there seems to be a clear relationship between acute physical exercise and BDNF release. BDNF plays key roles in neuron and glial cell development, the modulation of short- and long-term synaptic interactions, synaptic plasticity, and neuroprotection [5]. Several studies and reviews demonstrated that cognitive maturation was accompanied by BDNF expression in both the blood and cerebrospinal fluid [19]. Additionally, BDNF plays a crucial role in various stages of learning and memory processes [20]. Thus, high-intensity exercise may lead to improvements in cognitive performance due to the increase in BDNF and the molecular mechanisms that follow.

4.2. Influence of Cognitive Development on High-Performance Sports

In 2008, a study analyzed the role of corticospinal synaptic plasticity in high-performance athletes. Electrophysiological techniques and non-invasive imaging, such as transcranial magnetic stimulation, were used to activate corticospinal projections to specific muscles. These stimuli aimed to simulate the signals the brain receives from different types of motor training. Changes in cortical reorganization were observed, which were later associated with the acquisition of various mechanical skills [21]. It was also suggested that daily motor practice of the same movements could induce more lasting and even permanent changes in the corticospinal tract over time. In other words, the authors demonstrated the importance of synaptic plasticity in learning and acquiring new techniques.

One of the main functions of BDNF is regulating this synaptic plasticity. Therefore, BDNF may play a crucial role in professional athletes undergoing training and learning processes.

Recently, another study analyzed the functional and structural plasticity of the brains of elite karate athletes. Anatomical and functional maps were obtained again using magnetic resonance imaging. The images were segmented to differentiate between gray and white matter sections. The results were compared with volunteers who had not practiced sports regularly. Increases in the gray matter volume of karate athletes were revealed in various brain areas, such as the inferior and superior temporal cortex and the occipital cortex. White matter volume increases were also observed in the hypothalamus and caudate nucleus compared to the control group’s tests [22]. Recently, BDNF’s involvement in the trajectory of gray matter development has been demonstrated, due to its role in regulating neuronal and synaptic growth and plasticity [23]. Additionally, in the study with karate athletes, it was found that brain regions involved in movement planning and visual perception exhibited higher connectivity values. This suggests that BDNF may directly or indirectly participate in the cognitive maturation necessary to refine motor coordination in high-performance athletes.

In line with this study, in 2020, differences were assessed in the cognitive control processes (structural and functional aspects) between professional endurance runners and a healthy control group. Data extracted through multimodal magnetic resonance imaging were analyzed. The runners showed, at the cortical level, an increase in the gray matter volume of the left precentral gyrus, accompanied by greater functional connectivity with the right precentral and postcentral gyrus [24]. At the subcortical level, the runner group also showed a greater volume of gray matter in the left hippocampus. These results reinforce and demonstrate that high-performance athletes exhibit synaptic, structural, and functional modifications as a result of regular training. BDNF may be a cornerstone in these processes due to its neurogenic function.

A very recent study revealed a BDNF signature in transcriptomic analyses identifying the role of the basolateral amygdala in long-term memory. Specifically, BDNF participates in memory consolidation through its activity in long-term potentiation [25]. A 2022 review described the cognitive foundations of high-speed sports. Specifically, it showed how race car drivers needed a particularly well-developed long-term memory to perform basic actions within a circuit, such as braking, turning, accelerating, or taking a curve at a specific angle. The drivers established reference points they needed to remember to perform these movements [26]. In this way, BDNF and its role in memory development may play an important role in motorsports.

4.3. The Systemic Effects of BDNF Beyond the Nervous System

Beyond the nervous system, BDNF serves as a crucial mediator in various processes that benefit human health. Skeletal muscle is one of the primary sources of BDNF in the body and is therefore one of the tissues that most significantly interacts with this molecule. It has been demonstrated that high-intensity exercise, through fiber contraction, increases mRNA expression and thus BDNF levels in skeletal muscle cells. BDNF has been shown to influence signaling pathways related to lipid oxidation in skeletal muscle by enhancing AMPK signaling. AMPK phosphorylates acetyl-CoA carboxylase β, inhibiting its activity and reducing malonyl-CoA content. This reduction decreases the inhibition of carnitine palmitoyltransferase 1 and subsequently increases fatty acid oxidation [27].

Additionally, a recent study examined the role of BDNF in neuromuscular physiology, concluding that BDNF is essential for fiber-type specification and potential modulation. For instance, BDNF overexpression promoted a gene program specific to fast muscle fibers and increased the quantity of glycolytic fibers (those generating high power and rapid contractions). Conversely, reduced muscle BDNF levels resulted in a shift in muscle fiber composition, with type IIB fibers (fast and explosive) decreasing in favor of type IIX fibers, which have characteristics more geared toward endurance. This shift was accompanied by an increase in gene expression associated with endurance-related traits [28]. These findings suggest that the modulation of BDNF levels through exercise can influence skeletal muscle functionality and may hold therapeutic relevance in the treatment of muscle diseases, depending on specific pathological conditions.

The metabolic stress experienced by skeletal muscle cells during high-intensity exercise modifies, among other aspects, their mitochondrial content. Mitochondria are responsible for supplying the energy needed to withstand extreme conditions, such as strength or endurance training. Constant remodeling occurs through fusion, fission, or clearance processes, functioning as essential quality control mechanisms to eliminate damaged or non-functional mitochondria. A recent study demonstrated that BDNF released by muscles promotes this mitochondrial remodeling through the activation of the calmodulin kinase 2 β pathway and the AMP-activated protein kinase (AMPK) α subunit. Although it may seem counterintuitive, BDNF could play a fundamental role in energy supply during high-intensity exercise by mediating mitochondrial remodeling in skeletal muscle. Furthermore, excess fatty acids (e.g., due to obesity) in muscle tissue could disrupt mitochondrial quality control mechanisms. BDNF may also act as a myokine capable of maintaining the adaptive response to this lipid accumulation [29].

Moreover, beyond its role in mitochondrial dynamics, the recent literature has shown that BDNF is involved in other pathways of energy metabolism regulation. Its signaling in the hypothalamus may regulate energy homeostasis, body weight, and feeding behavior [30].

Another recent line of research suggested the importance of BDNF in cardiovascular function due to its interaction with vascular endothelial cells. Some studies have demonstrated that BDNF acts on the endothelium, promoting vascular angiogenesis and increasing capillary density. One study concluded that BDNF stimulates the formation of angiogenic tubes through the generation of reactive oxygen species derived from NADPH oxidase, mediated by the signaling transduction of its TrkB receptor. Additionally, it has been shown that its p75 receptor is also expressed in endothelial cells, which is associated with smooth muscle apoptosis. Several studies have revealed an overexpression of BDNF in patients who have experienced ischemic pathologies. BDNF may promote the survival of cardiomyocytes and enhance the expression of angiogenic factors under these conditions [31]. These findings would support the significance of physical exercise in individuals with cardiac ailments, as BDNF would act as a protective factor against such pathologies.

5. Limitations

In this review, we focused our analysis on the influence of BDNF on neuronal processes and its neuroplastic effects in the context of physical exercise. Although current evidence indicates that BDNF also plays a significant role in other systems, such as skeletal muscle, mitochondria, and the cardiovascular system, these effects were not the primary focus of our work. We recognize that this limits the integrative perspective on BDNF’s effects and suggests the need for studies that jointly address its systemic and not solely neural impacts. For this reason, we included an expanded discussion on the effects of BDNF in these other tissues and systems to provide a more comprehensive perspective and to suggest possible physiological implications beyond the neural scope.

6. Conclusions

BDNF is a neurotrophic factor of great importance in cognitive development. High-intensity physical exercise stimulates its release through mechanisms that have not yet been fully described. It has been suggested that lactate and the PGC-1α/FNDC5 pathway are involved in this process. However, some evidence indicated that cortisol, as a product of strenuous exercise, could inhibit lactate action and alter BDNF expression. This contrasts with the majority of results found in the reviewed studies. This discrepancy opens the door to new lines of research. Moreover, trials in high-performance athletes have revealed the importance of brain function in sports performance. An athlete’s learning or memory may be compromised by poor cognitive development. Given BDNF’s critical role in this aspect, it could guide the design of new training and wellness strategies. However, current experimentation is limited, and more extensive and detailed exploration is required to properly understand the underlying mechanisms that explain the inconsistencies found.