Excessive Exercise May Harm Brain Function

Exercise is widely recognized as a powerful way to prevent disease and promote health, including slowing age-related cognitive decline. Yet, some clinical studies have suggested a link between excessive exercise and reduced cognitive ability. Until now, the underlying mechanism remained unclear.

Researchers at Xiangya Hospital, Central South University, have uncovered a breakthrough. On December 3, 2025, the endocrinology team led by Luo Xianghang and Peng Hui published a paper in Cell Metabolism titled Excessive vigorous exercise impairs cognitive function through a muscle-derived mitochondrial pretender. Their findings reveal how overtraining damages cognitive function, offering new scientific evidence for the principle that “exercise should be moderate.” This study also explains why some high-intensity exercise enthusiasts experience memory decline.

Background

The “inverted U” or “J-shaped” relationship between exercise and health is not new in physiology. Extreme endurance training can lead to risks such as cardiac fibrosis and temporary immune suppression. Recent clinical observations have hinted that excessive exercise may also impair cognition, but the biological mechanism was unknown.

Scientists turned their attention to synapses, the microscopic foundation of cognitive function. Synapses rely heavily on nearby mitochondria for energy. When energy supply falters, synaptic structure and function deteriorate, marking the early stages of cognitive decline.

Another emerging area of research involves mitochondrial-derived vesicles (MDVs). These are small bubbles released under stress, carrying damaged mitochondrial proteins or DNA. They act as “stress messengers” between cells and organs. The potential impact of muscle-derived MDVs on the hippocampus, the brain’s memory hub, had not been studied until now.

Methods and Results

From Big Data to Mouse Models: Confirming the J-Shaped Curve

The team analyzed data from over 310,000 participants in the UK Biobank. After adjusting for age, education, and other factors, a clear J-shaped pattern emerged: overall physical activity was linked to cognitive risk, with vigorous exercise showing the strongest effect. The optimal dose was about 1216 metabolic equivalent minutes per week, roughly equal to four to five sessions of 30 minutes of high-intensity running. Beyond this threshold, cognitive risk increased.

In mouse models, animals subjected to excessive exercise showed significant learning and memory deficits in behavioral tests. Microscopy revealed reduced synaptic density and structural damage in the hippocampus, confirming that overtraining leads to synaptic loss and cognitive impairment.

Muscle-Derived Vesicles Cause Synaptic Dysfunction

Skeletal muscle, the primary organ of exercise, showed swollen mitochondria after overtraining. Blood tests revealed elevated levels of special vesicles rich in mitochondrial proteins and DNA, marked by PCNA-associated factors. The team named these vesicles “otMDVs.”

Experiments showed otMDVs could cross the blood-brain barrier and accumulate in hippocampal neurons. Injecting otMDVs into healthy mice caused synaptic loss and cognitive decline. Blocking otMDV production protected cognition even under excessive exercise, proving otMDVs are the key mediator of brain injury.

Lactate as the Trigger

The trigger for otMDV release was identified as lactate. Only prolonged, high-intensity exercise that sustained elevated lactate levels caused otMDV release. Direct lactate injection reproduced the effect, while reducing lactate production suppressed it. Mechanistically, lactate chemically modified the transcription factor ATF5, leading to abnormal protein and mtDNA packaging into otMDVs.

Dual Attack Mechanism

Once inside hippocampal neurons, otMDVs disrupted synapses in two ways:

1. Physical interference: PAF proteins hijacked anchoring sites meant for mitochondria, blocking energy supply.

2. Signal disruption: mtDNA activated inflammatory pathways that suppressed KIF5, the protein responsible for transporting mitochondria. This double hit caused an energy crisis and cognitive decline.

Broader Implications of Excessive Exercise

Beyond cognition, overtraining can harm the body in multiple ways:

• Liver fibrosis: Excess metabolic waste burdens the liver, increasing risk of fatty liver and cirrhosis.

• Accelerated aging: Oxidative stress damages DNA, leading to muscle loss and premature skin aging.

• Reduced immunity: Long-term intense exercise creates an “open window” period of lowered resistance, making infections more likely.

Key Takeaways: Exercise in Moderation

Professor Peng Hui emphasized: “The relationship between exercise and health follows a J-shaped curve. Moderate exercise brings the greatest benefits, but once the threshold is exceeded, the advantages quickly diminish and can even turn harmful.”

Excessive exercise does not refer to professional athletes’ training but rather to ordinary individuals pushing beyond safe limits, such as running more than 10 kilometers daily or training for hours without rest.

Practical Guidelines for Healthy Exercise

• Control intensity: Choose activities where you can still talk comfortably, such as brisk walking, jogging, swimming, or yoga.

• Manage duration: Adults should aim for 150–300 minutes per week, with sessions of 30–60 minutes.

• Prioritize recovery: Ensure 7–8 hours of sleep, replenish protein and fluids, and rest muscles for at least 48 hours.

• Listen to your body: Persistent fatigue, dizziness, or joint pain are warning signs of overtraining.

Health has no shortcuts. Quality and balance matter more than extreme duration or intensity.

Conclusion

This study reveals a complete chain of events linking excessive exercise to cognitive decline:
prolonged vigorous exercise → sustained lactate buildup in muscles → ATF5 modification → release of otMDVs carrying harmful proteins and DNA → otMDVs cross into the hippocampus → synaptic energy crisis and structural damage → impaired learning and memory.

The message is clear: in the pursuit of “higher, faster, stronger,” finding the balance where body and brain work in harmony is the true path to health.

Reference

[1] Huang Y, Hu B, Liu Y, Xie LQ, Dai Y, An YZ, Peng XY, Cheng YL, Guo YF, Kuang WH, Xiao Y, Chen X, Zheng YJ, Xie GQ, Wang JP, Peng H, Luo XH. Excessive vigorous exercise impairs cognitive function through a muscle-derived mitochondrial pretender. Cell Metab. 2025 Dec 3:S1550-4131(25)00486-3. doi: 10.1016/j.cmet.2025.11.002. PMID: 41344322.