Insight Into Muscle–Brain Crosstalk Could Lead to Novel Exercise and Pharmacologic Interventions for Aging-related Cognitive Impairment

Takeaways

• There is a well-established bidirectional relationship between physical activity, physical function, and brain health in older adults, and skeletal muscle is emerging as a novel source of neuroprotection in aging
• The 3rd International Research Symposium on Brain Health was titled “The Role of Muscle–Brain Crosstalk to Promote Healthy Aging”
• A key focus was the muscle secretome, particularly myokines and extracellular vesicles, as potential messengers influencing brain health
• The symposium identified critical takeaways and proposed next steps to clarify the mechanisms of muscle-to-brain crosstalk
• These pathways might be harnessed through exercise or pharmacologic interventions to promote brain health in older adults

Skeletal muscle is emerging as a promising target for preventing and treating cognitive impairment and dementia. Skeletal muscles produce and secrete myokines, proteins now known to have neuroprotective effects and mediate communication between muscles and the brain.

More recently, circulating extracellular vesicles (EVs), which encapsulate molecular cargo within a plasma membrane, have been demonstrated to carry signaling molecules between muscle and brain. Furthermore, “muscle clock” genes maintain circadian integrity and regulate sleep, both of which are important to brain health.

Clarifying the mechanisms of muscle-to-brain crosstalk might yield targets for preventing and treating aging-associated cognitive impairment and dementia. Toward that end, the 3rd International Research Symposium on Brain Health, sponsored by the Centre for Aging SMART at Vancouver Coastal Health and the University of British Columbia in Vancouver, was titled “The Role of Muscle–Brain Crosstalk to Promote Healthy Aging.”

This summary reports the key findings and recommendations on four main topics, reported in GeroScience, by Fabrisia Ambrosio, PhD, MPT, inaugural director of the Discovery Center for Musculoskeletal Recovery at the Schoen Adams Research Institute at Spaulding Rehabilitation, and colleagues.

Muscle Quality in Aging and Disease

Key Emphasis—Past assessments of muscle have focused principally on muscle mass and strength, but muscle quality, measured by myosteatosis, is one of the earliest changes in aging. Muscle quality strongly affects muscle strength, the risk of metabolic disorders, and systemic inflammation, all of which have causal relationships with cognition and dementia. 

Recommendations—Myosteatosis should be investigated as a predictor of cognition and brain health in aging populations. There is a critical need to develop targeted therapies and interventions that address myosteatosis in conjunction with muscle mass and function.

Epidemiological Association of Muscle Contractility and Brain Health

Key Emphasis—Most exercise interventions focus on sustained aerobic exercise, which primarily targets substrate metabolism and may have limited direct effects on myosteatosis. Resistance training, which influences changes to muscle fiber density, muscle fiber structure, and the muscle’s secretome, has been less studied in the context of brain health.

Recommendations—Clinical trials should assess the differential effects of resistance training and aerobic exercise on brain health. These trials should simultaneously evaluate the acute and chronic responses of myokines and EVs and their relationship to cognitive and brain health outcomes. A standardized definition of the stages of cognitive impairment and dementia should be incorporated, such as that jointly proposed by the National Institute on Aging and the Alzheimer’s Association. Resistance training protocols should distinguish between power, strength, and hypertrophy-focused interventions, as each may have distinct effects on myosteatosis and neuroprotection.

Circadian Rhythms and Muscle Clocks

Key Emphasis—Skeletal muscle circadian clocks are crucial to maintaining circadian rhythm integrity. Beyond exercise alone, optimization of diet, sleep regulation, and the timing of physical activity might improve muscle quality and its effects on brain health.

Recommendations—Conduct research to determine: (a) how skeletal muscle contributes to system-wide circadian regulation, (b) whether the molecular mediators involved in circadian signaling differ from those influencing cardiovascular, metabolic, and neurologic outcomes; and (c) how myosteatosis interacts with skeletal muscle clocks to affect brain function.

Molecular Mechanisms of Muscle–Brain Interactions

Key Emphasis—EVs are being explored as therapeutic candidates in brain disorders such as glioblastoma and stroke recovery. They might also have applications in treating neurodegenerative conditions, including Alzheimer’s disease. EVs can cross the blood–brain barrier, can be engineered with surface proteins to target specific payloads, and protect their cargo within the plasma membrane. 

Moreover, brain-derived EVs have been discovered, suggesting EVs participate in bidirectional communication between the brain and periphery. 

Recommendations—Investigate the potential for EVs to serve as therapeutic vectors and as molecular readouts, akin to a “liquid brain biopsy.” Move beyond imaging-based assessments of myosteatosis to identify myokine and EV biomarkers as more accessible, scalable methods to track muscle-related cognitive benefits.

The symposium report includes a figure that proposes a trajectory for research into muscle–brain crosstalk, hopefully leading to targeted exercise prescriptions, targeted muscle stimulation, and EV-based or myokine-enhancing drugs.