REF-454 · Hargreaves & Spriet, 2018 · Cold Spring Harbor Perspectives in Medicine, Vol. · Paper · PubMed
Exercise metabolism: fuels for the fire
Cold Spring Harbor review, predecessor to the 2020 Nature Metabolism review
Scope (abstract)
ATP supply during exercise comes from substrate-level phosphorylation (no oxygen needed) and from oxidative phosphorylation, which depends on oxygen delivery by the respiratory and cardiovascular systems and on reducing equivalents from carbohydrate, fat and — to a limited extent — protein stores
The relative contribution of these pathways is determined primarily by exercise intensity, and modulated by training status, preceding diet, age, gender and environmental conditions
Sustaining performance depends critically on optimal fuel (substrate) availability and use before, during and after exercise
Gives a short overview of exercise metabolism and covers in more depth how muscle glucose uptake, and fatty-acid uptake and oxidation, are regulated
Key Findings
A narrative review with no new data (from the abstract): the relative contribution of substrate-level and oxidative phosphorylation to ATP supply is primarily determined by exercise intensity, and modulated by training status, preceding diet, age, gender and environmental conditions.
The authors' conclusion: keeping exercise performance up depends critically on optimal substrate availability and use before, during and after exercise.
Relationship to REF-449
Same authors' earlier review. The 2020 Nature Metabolism paper REF-449 builds on it with updated literature and more attention to ergogenic interventions; for most contemporary purposes REF-449 supersedes REF-454. This 2018 paper spends more of its length on the regulation of glucose and fatty-acid uptake into muscle.
Practical Application
Narrative review (Hargreaves & Spriet 2018): the fuel mix during exercise is set primarily by intensity and modulated by training status, preceding diet, age, gender and environment; the authors state that optimal substrate availability before, during and after exercise is critical for maintaining performance. Use it as a secondary citation when REF-449 is already cited and the point is fuel regulation (glucose or fatty-acid uptake into muscle); it carries no protocol numbers.
The explicit list of modifiers (training status, diet, age, gender, environment) is a useful checklist when interpreting an athlete's metabolic test
Limitations
Narrative review, no systematic method; largely superseded by REF-449 for most practical purposes
Brief format
How this entry was checked and changed
Why this level
regraded 2026-09-27 from A: authoritative narrative review from the leading group, no systematic method
Content correction 2026-09-27
Level A -> B+ (narrative review from the leading group).
"More health/longevity context" -> abstract: a fuller section on how muscle glucose uptake and fatty-acid uptake/oxidation are regulated; Scope rewritten to the abstract, including the listed modifiers of fuel use.
Added Tier/Sport lines and an abstract-based Practical Application lead.
2026-09-28: added Key Findings from the abstract (Europe PMC PMID 28533314).