REF-458 · Richter & Hargreaves, 2013 · Physiological Reviews, Vol. · Paper · PubMed

Exercise, GLUT4, and skeletal muscle glucose uptake

Physiological Reviews synthesis of contraction-stimulated glucose transport

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

Scope (abstract)

How exercise-induced muscle glucose uptake is regulated. Glucose enters the muscle cell by facilitated diffusion through the GLUT4 transporter, which translocates from intracellular storage depots to the plasma membrane and T-tubules upon contraction. The review touches on glucose supply and metabolism briefly and concentrates on GLUT4 translocation and the molecular signalling that drives it during contraction.

Key Findings (concepts)

1

Acute regulation = GLUT4 translocation triggered by muscle contraction (insulin-independent)

2

Signalling is complex: AMPK, Ca²⁺ and NOS in the proximal part of the cascade; GTPases, Rab and SNARE proteins and cytoskeletal components in the distal part

3

Chronic regulation = GLUT4 expression, which is increased after exercise; AMPK and CaMKII appear to regulate GLUT4 transcription via the HDAC4/5–MEF2 axis (nuclear export of HDAC4/5 → histone hyperacetylation on the GLUT4 promoter)

4

Exercise training is the most potent stimulus to increase muscle GLUT4 expression — an effect that may partly explain improved insulin action, glucose disposal and enhanced muscle glycogen storage after training, in health and disease

Practical Application

Narrative review (Richter & Hargreaves 2013): muscle takes up glucose during exercise through GLUT4 transporters that move to the membrane on contraction, independent of insulin; exercise training is the most potent known stimulus for raising muscle GLUT4 expression, which may partly explain better insulin action, glucose disposal and glycogen storage in trained muscle. Meaning: the same mechanism that makes exercise a therapy for glucose control also makes trained muscle better at taking up and storing carbohydrate.
Inference, not tested here: contraction-driven uptake is why carbohydrate eaten during exercise reaches working muscle without an insulin surge (REF-066 for the intake evidence)
Inference, not tested here: the post-exercise period is a favourable window for glycogen restoration
Less directly performance-actionable, more health-applied

Limitations

Heavy molecular/cellular focus; narrative review, no systematic method
Less applicable to elite performance optimization than to metabolic health
2013 — later advances (TBC1D1, exerkines) underrepresented
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).
Key Concepts rewritten to the abstract's own content (proximal/distal signalling molecules, GLUT4 expression via HDAC4/5–MEF2, training as the most potent stimulus); "enhanced insulin sensitivity for hours after exercise" and the CHO-during-exercise justification relabelled as inference.
Added Tier/Sport lines and an abstract-based Practical Application lead.