The Muscle–Brain Connection: The Roles of BDNF, Irisin, and Exercise in Cognitive Health

How muscle-derived signals, kynurenine metabolism, and the preservation of muscle strength support memory, learning, and neuroplasticity

Abstract

In recent years, research in neuroscience, exercise physiology, and geriatric medicine has shown that communication between skeletal muscles and the brain extends far beyond the traditional role of muscles in movement and posture. Skeletal muscles are now recognized as biologically active tissues that can influence brain function, systemic inflammation, and cognitive health by releasing myokines and regulating metabolic pathways. Brain-derived neurotrophic factor (BDNF), the signaling molecule irisin, and the kynurenine metabolic pathway are especially important in this context. At the same time, reduced muscle mass and strength—particularly in the form of sarcopenia—has been associated with a higher likelihood of cognitive impairment in older adults. By reviewing biological mechanisms and clinical evidence, this article examines how physical activity and the preservation of muscle health may support memory, learning, and neuroplasticity.

Keywords: muscle–brain axis, BDNF, irisin, myokines, neuroplasticity, kynurenine, sarcopenia, exercise, cognitive health

Introduction and Medical Perspective

In modern medicine and neurophysiology, skeletal muscles are no longer viewed merely as mechanical structures responsible for movement. They are also recognized as active tissues involved in metabolic regulation and biological signaling. During contraction—especially during physical activity—muscles produce or release signaling molecules known as myokines. These molecules can act on several tissues, including the brain, and may participate in the regulation of inflammatory responses, energy metabolism, and processes related to cognitive function (1).

This two-way communication between muscles and the brain is known as the muscle–brain axis. It has become an important area of research in sports medicine, neuroscience, and gerontology. Understanding this axis may help explain part of the association between physical activity, the preservation of cognitive abilities, and the reduction of some adverse consequences of aging.

Myokine Secretion and Muscle-to-Brain Signaling

One molecule of particular interest in muscle–brain research is irisin, a protein derived from the precursor FNDC5 whose production may change in response to physical activity. Laboratory studies suggest that the FNDC5–irisin pathway may help regulate the expression of BDNF in the hippocampus (2).

The hippocampus is a key brain structure involved in memory formation, learning, and the consolidation of information. For this reason, the possible relationship between irisin and neurotrophic pathways has attracted considerable attention. However, evidence from cellular and animal studies must be distinguished from definitive findings in humans. Irisin release, post-exercise changes, and associations with cognitive function may vary according to exercise type, intensity, age, health status, and measurement methods.

Some studies have observed changes in circulating irisin after a single exercise session. However, a reported increase of approximately 17% in older adults should not be presented as a universal or definitive result without identifying the specific study, exercise protocol, and laboratory method.

Overall, current evidence supports the view that muscle contraction can influence brain function through biological signaling molecules and metabolic pathways. The precise contribution and clinical importance of each molecule in humans, however, remain under investigation.

The Essential Role of Brain-Derived Neurotrophic Factor

Brain-derived neurotrophic factor, or BDNF, is a member of the neurotrophin family. It contributes to neuronal growth and survival and helps regulate communication between neurons. It is particularly important in processes associated with learning and memory (6).

Memory and Learning

BDNF participates in the regulation of synaptic function and strengthens communication between nerve cells. These processes are essential for encoding new information, learning, and memory consolidation. The hippocampus is one of the brain regions with a central role in these mechanisms.

Neuroplasticity

Neuroplasticity is the nervous system’s ability to modify its structure and function in response to experience, learning, and the environment. By regulating several cellular signaling pathways, BDNF supports processes associated with synaptic plasticity. This allows the brain to adjust neural connections in response to new demands.

Neuronal Growth, Survival, and Health

BDNF helps maintain neuronal function and supports neuronal growth and survival. Its effects depend on the cell type, brain region, stage of development, and activation of relevant receptors. Its function should therefore not be reduced to one simple and uniform effect throughout the brain.

Supporting BDNF-Related Pathways

Regular physical activity—particularly aerobic exercise such as brisk walking, cycling, and swimming—may temporarily increase circulating BDNF under some conditions. Resistance exercise may also support cognitive health through several mechanisms, although BDNF responses depend on the exercise program, activity intensity, duration, and measurement method (5).

In addition to exercise, adequate and regular sleep, continued learning, social participation, and balanced nutrition are important components of a healthy lifestyle for maintaining brain function. These factors should not, however, be assumed to increase blood BDNF directly in every case or to act exclusively through this pathway.

Clinical Assessment of BDNF

BDNF is not a vitamin, medication, or dietary supplement. It is a naturally occurring protein in the body. Its concentration can be measured in biological samples, including blood, for scientific research; however, results may be affected by sampling conditions, sample processing, individual characteristics, and laboratory methods.

At present, blood BDNF measurement alone is not a standard diagnostic test for conditions such as depression, dementia, or memory disorders. Diagnosis should be based on clinical evaluation, medical history, examination, and appropriate investigations.

Skeletal Muscle as a Metabolic Processing and Inflammation-Regulating System

The role of muscle in the muscle–brain axis is not limited to the release of signaling molecules. Skeletal muscles also regulate the metabolism of various substances and can influence the profile of metabolites circulating in the blood.

An important pathway in this context is kynurenine metabolism. Kynurenine is produced during the breakdown of the amino acid tryptophan and can travel from the blood into the brain. Some metabolites in this pathway are associated with inflammatory processes and nervous-system function, although their effects vary according to the metabolite and biological context.

Preclinical studies indicate that activating metabolic programs in muscle—including pathways associated with the transcriptional coactivator PGC-1α1—can increase the expression of enzymes that convert kynurenine into other metabolites. This mechanism may limit the amount of kynurenine entering the brain and may protect against some adverse effects of stress (3). From this perspective, active muscle can be considered part of a system that regulates metabolism and the stress response. Describing muscle as an “inflammation filter,” however, is an explanatory analogy rather than a precise account of a single biological process. Neuroinflammation and systemic inflammation are controlled by complex networks of immune, neural, hormonal, and metabolic factors.

Sarcopenia and Its Association with Cognitive Impairment

Sarcopenia is a muscle disorder characterized by reduced muscle strength and a decline in muscle quantity or quality. It becomes more common with aging, but it is not an inevitable consequence of age. Physical inactivity, malnutrition, chronic disease, and metabolic changes can all contribute to its development.

Sarcopenia and Cognitive Health

Observational studies and systematic reviews have reported an association between sarcopenia and a greater likelihood of cognitive impairment. Such impairment may affect memory, attention, information-processing speed, planning, and other executive functions. Statistical association does not, however, prove causation. Physical inactivity, vascular disease, depression, malnutrition, and chronic illness may simultaneously affect muscle strength and cognitive function.

Some reports and meta-analyses have suggested a substantial association between sarcopenia and cognitive impairment. To state precisely that the risk or likelihood is approximately doubled, the relevant study, the number of included investigations, the definition of sarcopenia, the statistical measure, and its confidence interval must be identified. A general reference to a 2025 meta-analysis without traceable bibliographic details is insufficient to verify this figure independently.

Resistance Training and Physical Activity in Older Adults

Resistance training—including exercises using weights, resistance bands, or body weight—is an important method for preserving muscle strength and function in older adults. Aerobic exercise, balance training, and combined activities may also support general health, mobility, and independence.

Systematic reviews suggest that physical activity may improve some aspects of cognitive performance in adults over 50 under certain conditions. The effect depends on exercise type, intervention duration, baseline status, and the cognitive assessment used (5).

Exercise programs for older adults should be adapted to physical capacity, cardiovascular status, balance, and underlying medical conditions. People with severe weakness, a history of falls, or significant illness should consult a physician or physiotherapist before beginning an exercise program.

Conclusion and Practical Message

The muscle–brain axis is a clear example of interaction between different body systems. Through myokine secretion, metabolic regulation, and effects on inflammatory responses, skeletal muscles can contribute to nervous-system health. BDNF is an important protein that supports neuroplasticity, learning, and memory, while the FNDC5–irisin pathway and kynurenine metabolism are prominent mechanisms under investigation in this field.

Preserving muscle strength and mass is especially important in older age because sarcopenia is associated with adverse physical outcomes and a greater likelihood of cognitive impairment. Available evidence supports regular physical activity, resistance exercise adapted to individual ability, adequate sleep, balanced nutrition, and continued learning as important components of a healthy lifestyle.

The central message is that muscle health matters not only for movement and physical independence but also as part of a comprehensive approach to supporting brain health and quality of life across the lifespan. Exercise should be regarded as a strategy for improving general health and reducing certain risk factors—not as a guaranteed method of preventing dementia or treating cognitive disorders.

References

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