Purpose <p>To revisit the anticipatory regulation model of exercise in heat and show how contemporary molecular evidence, particularly transient receptor potential (TRP) channels provide a plausible mechanistic basis for trajectory-sensitive regulation beyond than classic cellular catastrophe or limitation paradigm.</p> Approach <p>By synthesising self-paced and fixed-rating of perceived exertion (RPE) findings with recent molecular and integrative physiology, it proposes a closed-loop framework where thermal signals from muscle/skin are transduced by TRPs and integrated centrally to shape pacing in real time.</p> Evidence <p>Evidence consistent with anticipatory regulation includes earlier environment-sensitive reductions in power and skeletal muscle electromyography before lethal core temperature divergence, RPE-clamp profiles that align subsequent heat storage across conditions, and field data showing pace selection that preserves safe heat-storage trajectories. At the molecular level, TRPV1 in skeletal-muscle sarcoplasmic reticulum links rising local temperature to Ca²⁺, signals then downstream leading to PGC-1α signalling promoting mitochondrial biogenesis and endurance capacity, while group III/IV afferents convey thermal/metabolic state to the central nervous system. Warm-sensitive TRPs in hypothalamic circuits operate near physiological brain temperature and contribute to thermoeffector drive, completing a periphery - central feedforward/feedback loop.</p> Conclusions <p>A thermo-TRP closed loop framework can reconcile “integrated strain” and anticipatory models as different descriptions of the same system while clarifying the boundary between evidence and biological plausibility when extrapolating from molecular studies to whole body regulation. This framework yields testable predictions and clarifies why interventions such as skin cooling and heat acclimation improve safety margins by altering thermal trajectory, not just peak core temperature.</p>