What Causes Muscle Fatigue According to Science

Medically Reviewed by Ian Nathan, MBChB, on 5th February 2026

Muscle fatigue is a universal human experience, occurring during intense exercise, prolonged physical activity, and sometimes even routine daily tasks.

While many people attribute fatigue solely to “lactic acid buildup,” modern physiology shows that the process is far more complex. Muscle fatigue arises from an interaction between energy depletion, metabolic byproducts, nervous system regulation, electrolyte balance, oxygen delivery, and structural stress within muscle fibers.

This article examines muscle fatigue through the lens of scientific research, explaining the cellular, metabolic, neurological, and systemic mechanisms that reduce force production and endurance capacity during physical exertion.

Understanding Muscle Fatigue

Muscle fatigue is defined as a reversible decline in the ability of a muscle to generate force or power. It does not necessarily mean complete exhaustion; rather, it reflects reduced performance capacity compared to baseline.

Researchers broadly classify fatigue into two overlapping categories: peripheral fatigue, which originates within the muscle tissue itself, and central fatigue, which involves reduced neural drive from the brain and spinal cord.

In most real-world situations, both mechanisms occur simultaneously. For example, during a long-distance run, metabolic changes inside muscle fibers coexist with altered neurotransmitter signaling in the central nervous system.

Energy Systems and ATP Depletion

All muscle contraction depends on adenosine triphosphate (ATP), the primary energy currency of the cell. ATP fuels the actin-myosin cross-bridge cycle that produces force.

During exercise, ATP is continuously broken down into adenosine diphosphate (ADP) and inorganic phosphate. The body must rapidly regenerate ATP to sustain contraction.

There are three primary ATP regeneration systems:

• The phosphocreatine (ATP-PCr) system for short, explosive activity
• Anaerobic glycolysis for moderate-to-high intensity efforts
• Aerobic oxidative phosphorylation for sustained endurance activity

When ATP regeneration fails to keep pace with demand, force production declines and fatigue develops.

Phosphocreatine Depletion in High-Intensity Exercise

Phosphocreatine acts as an immediate buffer to rapidly regenerate ATP during short bursts of maximal effort, such as sprinting or heavy resistance training.

However, phosphocreatine stores are limited and can decline substantially within 10-30 seconds of maximal exertion.

Once depleted, muscles rely more heavily on slower ATP-producing pathways, leading to reduced peak power output. Full phosphocreatine restoration requires oxygen and typically several minutes of recovery.

Metabolic Byproducts and Intracellular Acidosis

The long-standing belief that lactate directly causes muscle fatigue has been largely revised. Lactate itself is not toxic; in fact, it serves as a usable fuel source for other tissues.

Instead, the accumulation of hydrogen ions during rapid glycolysis leads to decreased intracellular pH (metabolic acidosis).

This acidic environment interferes with key processes such as calcium binding and enzyme activity, reducing contractile efficiency and contributing to the sensation of muscular “burn.”

Inorganic Phosphate Accumulation

Inorganic phosphate (Pi), released during ATP breakdown, accumulates during high-intensity exercise.

Elevated Pi levels impair cross-bridge cycling and interfere with calcium release from the sarcoplasmic reticulum.

This mechanism is now considered one of the primary contributors to short-term peripheral fatigue.

Calcium Handling and Excitation-Contraction Coupling

Muscle contraction depends on precise regulation of calcium ions. When a nerve impulse reaches a muscle fiber, calcium is released from the sarcoplasmic reticulum into the cytoplasm.

During prolonged or repeated contractions, calcium release becomes less efficient, and reuptake mechanisms may slow.

This disruption impairs excitation-contraction coupling, reducing force production even if ATP remains available.

Glycogen Depletion and Endurance Fatigue

Muscle glycogen is a major fuel source during moderate-to-high intensity activity.

During prolonged exercise lasting longer than 60-90 minutes, glycogen stores progressively decline.

Low glycogen availability reduces ATP production capacity and is strongly associated with endurance fatigue and the phenomenon athletes describe as “hitting the wall.”

Carbohydrate intake during extended activity has been shown to delay fatigue by preserving glycogen and maintaining blood glucose levels.

Oxygen Delivery and Cardiovascular Limitations

For sustained exercise, oxygen delivery becomes a limiting factor. The cardiovascular system must transport oxygen to working muscles to support aerobic metabolism.

If oxygen supply does not meet metabolic demand, reliance on anaerobic pathways increases, accelerating metabolite accumulation.

Higher cardiorespiratory fitness improves oxygen extraction and utilization, thereby delaying fatigue onset.

Electrolyte Balance and Neuromuscular Function

Electrolytes such as sodium, potassium, calcium, and magnesium are essential for action potential generation and muscle contraction.

During prolonged sweating, electrolyte losses may alter nerve conduction and muscle excitability.

Although severe electrolyte imbalance is uncommon in recreational exercise, inadequate hydration and sodium replacement during prolonged endurance events can impair performance.

Central Nervous System Fatigue

Central fatigue refers to a reduction in voluntary neural activation of muscles.

Changes in neurotransmitters such as serotonin, dopamine, and noradrenaline influence motivation, mood, and perceived effort.

The brain may reduce motor output as a protective mechanism to prevent physiological damage, a concept known as the “central governor” theory.

This explains why perceived exertion can increase even before muscles are metabolically exhausted.

Psychological and Cognitive Influences

Mental fatigue, sleep deprivation, and stress can significantly impair physical performance.

Research demonstrates that cognitive exhaustion increases perceived effort and reduces endurance time, even when physiological markers remain unchanged.

This interaction between mind and muscle highlights the integrated nature of fatigue.

Muscle Damage and Inflammation

Unaccustomed or high-intensity exercise can cause microscopic damage to muscle fibers.

This structural stress triggers inflammatory responses and contributes to delayed-onset muscle soreness (DOMS).

Although soreness and fatigue are distinct phenomena, inflammation and tissue repair temporarily reduce strength and performance capacity.

Temperature and Heat Stress

Environmental heat increases cardiovascular strain and accelerates dehydration.

Elevated core temperature can impair central nervous system function and increase perceived effort.

Heat-related fatigue is therefore a combination of metabolic strain and thermoregulatory stress.

Hormonal Responses to Prolonged Exercise

Exercise triggers hormonal changes including elevations in cortisol, adrenaline, and growth hormone.

While these adaptations support energy mobilization, chronically elevated stress hormones may contribute to overtraining-related fatigue.

Adequate recovery and sleep are critical for hormonal balance.

Overtraining and Chronic Fatigue

When training volume or intensity exceeds recovery capacity, persistent fatigue can develop.

Symptoms may include reduced performance, mood disturbance, sleep disruption, and prolonged soreness.

Gradual progression, rest days, and structured recovery strategies help reduce overtraining risk.

Age and Muscle Fatigue

Aging is associated with changes in muscle mass, mitochondrial function, and neuromuscular signaling.

Older adults may experience fatigue at lower absolute workloads, although regular resistance and endurance training can mitigate these effects.

Maintaining physical activity supports mitochondrial health and delays age-related performance decline.

Medical Conditions That Influence Fatigue

Chronic illnesses such as anemia, hypothyroidism, diabetes, and heart failure can impair oxygen delivery or energy metabolism.

Persistent or unexplained muscle fatigue should be evaluated medically, especially if accompanied by weakness, weight changes, or systemic symptoms.

Addressing underlying health conditions often improves exercise tolerance.

Recovery and Prevention Strategies

Muscle fatigue is reversible with adequate recovery.

Key strategies include:

• Adequate carbohydrate intake to restore glycogen
• Sufficient protein to support muscle repair
• Hydration and electrolyte replacement
• High-quality sleep for neural and hormonal recovery
• Periodized training programs that balance stress and rest

Optimizing muscle recovery reduces cumulative fatigue and improves long-term performance outcomes.

Key Takeaways from the Evidence

• Muscle fatigue results from both peripheral and central mechanisms
• ATP depletion and phosphocreatine reduction limit short-term high-intensity output
• Glycogen depletion is a primary driver of endurance fatigue
• Electrolyte balance, hydration, and oxygen delivery influence performance
• Psychological and neurological factors significantly affect perceived effort

Conclusion

Muscle fatigue is a multifactorial physiological process involving metabolic, neural, cardiovascular, and structural factors.

Rather than being caused by a single substance such as lactate, fatigue reflects the body's integrated response to energetic demand and physiological stress.

Understanding these mechanisms allows individuals to train intelligently, optimize recovery, and recognize when fatigue signals normal adaptation versus potential medical concern.

References

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2. Fitts RH. The cross-bridge cycle and muscle fatigue. Physiol Rev.
3. Gandevia SC. Spinal and supraspinal factors in human muscle fatigue. Physiol Rev.
4. Coyle EF. Substrate utilization during exercise. Med Sci Sports Exerc.
5. Sawka MN, et al. Exercise and fluid replacement. Med Sci Sports Exerc.