How do leg muscles impact brain health?

How Leg Muscles Impact Brain Health

Leg muscle activity through structured exercise—particularly resistance training involving major muscle groups—directly enhances cognitive function and brain health through multiple biological mechanisms, with resistance exercise showing superior effects compared to other exercise modalities. 1

Primary Mechanisms of Muscle-Brain Communication

Skeletal muscle contraction, especially in large leg muscles, triggers a cascade of protective effects on the brain through several pathways:

Myokine Secretion

• Contracting leg muscles secrete myokines (protein hormones) that cross the blood-brain barrier and directly influence brain function. 2
• Cathepsin B, released during muscle contraction, passes through the blood-brain barrier to enhance brain-derived neurotrophic factor (BDNF) production, which promotes neurogenesis, memory, and learning. 2
• The myokine FNDC5 (encoded by the PGC1α-dependent gene) likewise contributes to increased BDNF levels in the brain. 2
• IL-6 levels increase with exercise and may contribute to central nervous system regulation. 2

Neuroprotective Metabolic Shifts

• Leg muscle exercise increases PGC1α-dependent expression of kynurenine aminotransferase enzymes, which shifts the balance from neurotoxic kynurenine toward neuroprotective kynurenic acid, reducing depression-like symptoms. 2
• This metabolic crosstalk represents a direct muscle-brain endocrine loop that protects against neurological decline. 2, 3

Mitochondrial Protection

• Physical exercise involving leg muscles antagonizes brain mitochondrial dysfunction by reducing reactive oxygen species production, improving antioxidant capacity, and decreasing oxidative damage. 4
• Exercise activates signaling pathways that reduce apoptotic signaling and neuronal death while maintaining brain ATP production. 4

Optimal Exercise Prescription for Brain Health

Resistance Training Shows Superior Effects

• Recent network meta-analysis evidence demonstrates that resistance exercise produces superior cognitive benefits compared to aerobic or other exercise modalities in older adults. 1
• The WHO recommends muscle-strengthening activities involving major muscle groups (including legs) at least three times per week. 1

Dose-Response Relationship

• There is no minimal threshold for beneficial effects of leg muscle exercise on cognition—benefits begin immediately. 1
• The estimated minimal exercise dose for clinically relevant cognitive changes is 724 METs-min per week. 1
• Doses beyond 1200 METs-min per week provide diminishing returns. 1
• Clinically important effects occur at lower doses when using resistance training compared to other modalities. 1

Practical Implementation

• Adults should engage in 150-300 minutes per week of moderate-intensity aerobic activity OR 75-150 minutes of vigorous-intensity aerobic activity. 5
• Combine aerobic activity with strength training and flexibility exercises for optimal brain protection. 5
• Resistance training should include 1 set of 8-10 different exercises involving major muscle groups (including legs) performed 2-3 days per week. 1

Specific Brain Benefits from Leg Muscle Activity

Cognitive Function Enhancement

• Exercise improves overall cognition, attention/concentration, and visuospatial/executive function. 1
• A 44.5% reduction in the proportion of patients meeting criteria for mild cognitive impairment has been observed after combined aerobic and resistance training. 1
• Enhanced physical activity improves cognitive function even in older adults without known impairment. 1

Structural Brain Protection

• Exercise preserves brain volume, especially hippocampal volume. 6
• Physical activity reduces risk of silent brain infarcts in older adults. 1
• Exercise modulates functional connectivity, neuronal compensation, resource allocation, and neuronal efficiency. 6

Vascular and Metabolic Benefits

• Leg muscle exercise improves insulin sensitivity, which protects against vascular dementia. 1
• Exercise reduces cardiovascular risk factors (hypertension, dyslipidemia, diabetes) that contribute to cognitive decline. 1
• Structured aerobic exercise enhances vascular health in stroke survivors. 1

Clinical Pitfalls to Avoid

Common mistakes when prescribing exercise for brain health:

• Focusing exclusively on aerobic exercise while neglecting resistance training—resistance training shows superior cognitive benefits. 1
• Treating all exercise doses as equivalent—the dose-response relationship is non-linear and exercise-type dependent. 1
• Recommending only high-intensity programs—lower doses of resistance training can achieve clinically meaningful benefits. 1
• Ignoring adherence strategies—interventions promoting daily activity integration (like walking) show better long-term adherence than facility-dependent programs. 5

Special Populations

Cognitive Impairment and Dementia

• Multicomponent exercise is most effective for mild cognitive impairment. 1
• Resistance exercise is best for established dementia. 1
• High-dose interventions (>150 min/week) are no more effective than low-dose ones (<150 min/week) in cognitively impaired adults. 1

Women vs. Men

• Exercise shows superior cognitive effects in older women compared to older men. 1
• Biological sex may moderate the dose-response relationship between exercise and cognition. 1

Post-Stroke Survivors

• Physical activity reduces risk of cognitive impairment and vascular dementia in stroke survivors. 1
• Combined aerobic and resistance training improves cognition and reduces mild cognitive impairment prevalence. 1