Glycogen Depletion, Nutritional Ketosis, and Exercise Fatigue: Novel Assessment Methods and Psychobiological Mechanisms

Skeletal muscle glycogen is a major endogenous carbohydrate store and an important substrate for ATP resynthesis during exercise. Its utilization increases with exercise intensity and duration, and low muscle glycogen availability has long been associated with impaired endurance exercise capacity. Beyond its role as a metabolic substrate, glycogen availability may influence excitation-contraction coupling and Ca²⁺ handling, providing multiple mechanisms through which carbohydrate availability can affect contractile function and fatigue.

Ketogenic diets (KD), characterized by severe carbohydrate restriction (<5% of energy intake), induce a profound redistribution of exercise metabolism. Reduced carbohydrate availability markedly increases fat oxidation while decreasing reliance on carbohydrate and muscle glycogen during exercise. This adaptation has frequently been interpreted as a glycogen-sparing mechanism that could extend endogenous carbohydrate availability during prolonged exercise. However, reduced glycogen utilization does not necessarily imply glycogen preservation, particularly when exercise begins with substantially lower muscle glycogen stores. Direct evidence quantifying muscle glycogen before and after a standardized exercise bout during ketogenic adaptation remains limited.

The marked shift toward lipid oxidation may also have consequences for exercise energetics. Fat oxidation provides less ATP per unit of oxygen consumed than carbohydrate oxidation, thereby increasing the oxygen requirement for a given rate of oxidative ATP resynthesis. This may become particularly relevant as exercise intensity and ATP demand increase, when carbohydrate-derived energy provision becomes progressively more important. Thus, ketogenic adaptation may reduce glycogen utilization while simultaneously increasing the oxygen cost of exercise and limiting the capacity to sustain higher exercise intensities. Nutritional ketosis may additionally influence exercise responses beyond skeletal muscle metabolism. KD markedly increases circulating β-hydroxybutyrate (βHB), which can be utilized as an oxidative substrate by peripheral tissues and crosses the blood-brain barrier, contributing to cerebral oxidative metabolism. Whether increased ketone availability modifies the cerebral response to exercise, and whether this relates to perceptual or exercise responses during carbohydrate restriction, remains unclear.

Our MAIN HYPOTHESIS is that short-term ketogenic adaptation induces a rapid shift from carbohydrate toward lipid-derived energy provision but that reduced glycogen utilization does not preserve absolute muscle glycogen availability. We further hypothesize that this metabolic redistribution increases the oxygen requirement of prolonged exercise and impairs exercise capacity, particularly as energetic demand increases.

Using a randomized controlled dietary intervention in endurance-trained athletes, we will pursue the following specific aims:

1. To determine the effects of 10 days of ketogenic adaptation on skeletal muscle glycogen availability and utilization during standardized prolonged exercise. We hypothesize that KD reduces resting muscle glycogen and attenuates exercise-induced glycogen utilization, without preserving post-exercise glycogen availability.
2. To determine how ketogenic adaptation influences substrate oxidation, exercise energetics, and exercise capacity. We hypothesize that the shift toward greater lipid oxidation increases the oxygen cost of standardized submaximal exercise and impairs both prolonged exercise tolerance and subsequent high-intensity endurance capacity.
3. To explore circulating substrate, perceptual, and cerebral responses to exercise during nutritional ketosis. We will characterize glucose, lactate, and βHB responses and assess prefrontal cortical oxygenation using functional near-infrared spectroscopy (fNIRS), providing an exploratory assessment of whether the pronounced peripheral metabolic adaptations are accompanied by detectable alterations in cerebral hemodynamic or perceptual responses.