REF-449 · Hargreaves & Spriet, 2020 · Nature Metabolism, Vol. · Paper · PubMed

Skeletal muscle energy metabolism during exercise

Nature Metabolism narrative review of ATP resynthesis, substrate utilization and ergogenic interventions

B+moderate evidenceMeasured on a mixed groupWritten before October 2026, being re-checked

Scope

Overview of how skeletal muscle resynthesizes ATP across the exercise intensity–duration spectrum, of the regulatory mechanisms that match ATP resynthesis to ATP demand, and of interventions that target muscle metabolism for ergogenic benefit in athletic events. Written for events lasting seconds to several hours.

The base's standard citation for "how substrate metabolism works during exercise"; the numbers behind it live in the primary studies it draws on (REF-450, REF-451, REF-452).

Key Findings (concepts)

1. ATP supply pathways:

Muscle ATP stores are small, so metabolic pathways must be activated to maintain the required rate of ATP resynthesis
Phosphocreatine breakdown and muscle glycogen breakdown → substrate-level phosphorylation ("anaerobic")
Oxidative phosphorylation using reducing equivalents from carbohydrate and fat metabolism ("aerobic")
The relative contribution of these pathways is determined primarily by the intensity and duration of exercise
Carbohydrate is the main fuel for both anaerobic and aerobic metabolism in most Olympic events

2. Substrate crossover (concept; the numbers are not in this abstract):

Fat oxidation dominates at low intensity and carbohydrate dominates at high intensity; the intensity where carbohydrate overtakes fat is the "crossover"
Not from this paper: the tracer data behind the crossover are in Romijn 1993 REF-450 (25, 65 and 85% VO₂max) and the measured FatMax in trained men is in Achten & Jeukendrup 2003 REF-451 (0.52 g/min at 62.5% VO₂max in 55 men)

3. Glycogen:

Muscle glycogen is the main carbohydrate store for exercise; its depletion limits work capacity (the original biopsy evidence is Bergström & Hultman 1967 REF-452)
Store sizes, depletion times and the "fatigue after X minutes" figures that used to be listed here are not in the abstract and were removed

4. Lactate (modern view, as in the review's framing):

Not a waste product; an exchangeable fuel between tissues, a gluconeogenic precursor and a signalling molecule (see Brooks REF-172, REF-471)

5. Regulatory mechanisms (topics covered; the abstract names no specific pathway):

Ca²⁺-linked activation of glycogen phosphorylase, adrenergic activation of lipolysis, AMPK, PDH regulation, fatty-acid transport (CD36 / CPT1) — (full text; not checked against the abstract)

6. Ergogenic interventions (the review "summarizes various interventions that target muscle metabolism"):

Carbohydrate during exercise (see REF-066), caffeine, creatine, β-alanine, bicarbonate, nitrate, ketone supplements — (full text; not checked against the abstract). Evidence grades and event-duration windows for each are NOT from this paper; use the supplement entries and the IOC consensus REF-358

Practical Application

Narrative review (Hargreaves & Spriet 2020): during exercise ATP is resynthesized from phosphocreatine and glycogen breakdown ("anaerobic") and from oxidative phosphorylation of carbohydrate and fat ("aerobic"); the mix is set primarily by exercise intensity and duration, and for most Olympic events carbohydrate is the primary fuel for both. Use it as the mechanism reference when explaining why fueling and intensity-specific substrate use matter; quote the numbers from the primary studies (REF-450, REF-451, REF-452), not from this entry.
Explains why fasted or low-glycogen Z2 work shifts the fuel mix toward fat (practical protocols: REF-157)
Explains the logic of glycogen loading and of carbohydrate during long events (REF-066, SYNTH-04)
Background for discussing ergogenic supplements (REF-358)

Limitations

Review, not new empirical data; no systematic method
Heavy emphasis on muscle-level biochemistry, less on whole-body integration
Does not address sex-specific differences or aging effects on substrate metabolism
Evidence base up to 2020
Focus on Olympic events; less ultra-endurance specificity
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; "1145+ citations" is not an evidence grade and was removed).
All numeric content (PCr 0-10 s / ~30 s, 25% / 55-65% / 75-85% VO₂max bands, 60-70% and 95-100% energy shares, 0.5-1.0 g/min, 400-500 g and 80-100 g glycogen, 1600-2000 / 400 kcal, 70-80% VO₂max, >90 min, >60-90 min, 1-4 min) -> not in the abstract; removed. Crossover and FatMax figures now point to the entries that carry them (REF-450, REF-451).
"Caffeine — Tier A", "Creatine — Tier A" -> evidence grades are not from this paper; removed. Ergogenic list kept as topics only, marked full text.
Added Tier/Sport lines and a Practical Application lead that states the abstract's finding.