Caffeine, skeletal muscle signalling, and exercise adaptation: a narrative review separating acute ergogenic effects...

Caffeine is one of the most widely used and extensively studied ergogenic aids in sport, yet whether its well-established acute benefits extend to the chronic remodelling of skeletal muscle remains unresolved. In this narrative review, we distinguish the acute ergogenic effects of caffeine from its potential influence on chronic skeletal muscle remodelling, because the mechanisms that improve acute performance need not be those that govern repeated tissue adaptation. The evidence for acute ergogenicity rests on a large human literature, in which adenosine receptor antagonism is the probable dominant mediator, with additional contributions from potassium handling, ryanodine receptor 1 (RyR1) sensitisation, altered contractile behaviour, and reduced perceived effort. Evidence that repeated caffeine exposure around exercise modifies chronic skeletal muscle adaptation in humans remains limited; available training trials are short, narrow in modality, and lack muscle biopsy endpoints, and several acute endurance studies under substrate restriction are better interpreted as training quality mediator evidence. Preclinical work is more mechanistic but directionally mixed, supporting Ca²⁺ linked CaMKKβ (Ca²⁺/calmodulin-dependent protein kinase kinase β) and AMP-activated protein kinase (AMPK) signalling, autophagy, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) related transcription, and mitochondrial quality control on one side, and raising an attenuation hypothesis through protein synthesis, recovery, and tissue-specific remodelling on the other. We therefore evaluate three working models in which caffeine acts as an amplifier, a partial mimic, or an attenuator of exercise-related signalling. Current human evidence is most compatible with partial mimicry and training quality mediation rather than direct amplification or impairment of long-term tissue adaptation. Resolving this question will require human training studies that combine muscle biopsy endpoints, caffeine-abstinent post-training testing, objective sleep monitoring, and explicit control of external training load. On balance, the current evidence supports interpreting caffeine as a reliable acute ergogenic aid and a plausible mediator of training quality, rather than as a proven direct modifier of chronic skeletal muscle adaptation.