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Introduction

For more than half a century, exercise science has largely explained fatigue through one dominant idea: that physical performance declines because working muscles run out of glycogen. This belief has shaped dietary guidelines, fueling strategies, and the widespread emphasis on high carbohydrate intake during prolonged exercise.

A comprehensive review published in Endocrine Reviews revisited this assumption by analyzing more than 100 years of experimental research, encompassing over 160 controlled studies examining carbohydrate ingestion, metabolism, and physical performance. Rather than focusing on a single protocol or population, the authors synthesized data across exercise intensities, dietary conditions, and metabolic states to reassess what consistently predicts performance decline.

What the Data Showed

Across the studies reviewed, one pattern appeared repeatedly: exercise termination was more closely associated with declining blood glucose than with muscle glycogen depletion. In multiple trials, individuals stopped exercising while measurable glycogen remained in working muscle, yet blood glucose had fallen to low levels.

The review also highlights that muscle ATP concentrations remain stable at the point of fatigue, and that no studies document muscle rigor or catastrophic energy failure during voluntary exercise. This observation challenges the long-standing “energy crisis” explanation, which would predict ATP depletion if muscle fuel exhaustion were the primary cause.

Finally, when carbohydrate intake during exercise was manipulated, higher doses did not reliably produce greater performance benefits. Low carbohydrate intakes frequently produced similar outcomes to much larger intakes, a pattern inconsistent with the idea that carbohydrates improve performance by directly supplying muscle fuel.

Mechanisms & Physiology

A. Blood Glucose and Central Fatigue

The brain relies heavily on glucose to sustain neural activity. The review emphasizes that falling blood glucose activates protective neural responses designed to preserve brain function. As glucose availability declines, the nervous system appears to limit motor unit recruitment, reducing force output and voluntary effort.

Importantly, this regulation does not require overt symptoms of hypoglycemia. The authors note that relative drops in blood glucose, even before clinical hypoglycemia thresholds are reached, can influence neural signaling and perceived fatigue.

B. Muscle Glycogen, ATP, and the “Energy Crisis” Theory

A central claim of the review is that the traditional energy crisis model lacks biological support. If muscle glycogen depletion caused fatigue through ATP failure, one would expect declining ATP levels and impaired contractile function. However, across decades of biopsy and metabolic data, ATP levels are preserved at fatigue, even during prolonged or intense exercise.

The absence of muscle rigor further weakens the energy crisis explanation. Rigor is a predictable outcome of severe ATP depletion, yet it has never been observed in voluntary exercise fatigue. This suggests that fatigue reflects regulation, not mechanical failure.

C. Substrate Use: Carbs vs. Fat During Prolonged Exercise

The review documents that as exercise progresses, fat oxidation increases, often providing a substantial proportion of total energy expenditure, even at higher intensities. In some studies, fat supplied more energy than carbohydrates at the point of exhaustion.

Additionally, athletes adapted to low-carbohydrate diets demonstrated exceptionally high fat oxidation rates while maintaining comparable performance outcomes. These findings challenge the idea that carbohydrates are an obligatory fuel source once intensity exceeds a certain threshold.

Practical Implications

While the review primarily examines prolonged exercise, its findings offer broader insight into how fatigue is regulated during sustained physical effort. The data suggest that systemic glucose availability, rather than local muscle fuel depletion, plays a central role in performance regulation.

The review also highlights substantial inter-individual variability. Some individuals maintain blood glucose effectively during exercise without carbohydrate intake, while others experience earlier declines. This variability may help explain inconsistent responses to standardized fueling strategies.

Importantly, the findings do not argue against carbohydrate use altogether. Instead, they suggest that the mechanism of benefit differs from traditional explanations, operating through blood glucose maintenance rather than direct muscle refueling.

The Bottom Line

This review concludes that blood glucose regulation is a more consistent predictor of performance decline than muscle glycogen depletion across a century of exercise research. Rather than failing due to a muscular energy shortage, fatigue appears to reflect centrally mediated regulation aimed at preserving systemic and neural stability during prolonged exertion.

By reframing the role of carbohydrates from muscle fuel to glucose stabilizer, the analysis invites a reassessment of how decades of performance data are interpreted, without overturning the value of carbohydrates, but by clarifying their primary physiological role.

Reference

Carbohydrate Ingestion on Exercise Metabolism and Physical Performance
Endocrine Reviews
DOI: 10.1210/endrev/bnaf038