Sarcolipin-SERCA uncoupling as a plausible heat source for sustaining fever.

Fever is an evolutionarily conserved host defence that elevates defended core temperature and metabolic rate, yet the dominant thermogenic tissue sustaining febrile heat production in adult mammals remains unresolved. Brown adipose tissue and shivering thermogenesis are emphasized in classical models, but adult BAT is quantitatively limited, and shivering is often intermittent and behaviourally costly. Because skeletal muscle is high-mass and widely distributed, skeletal muscle non-shivering thermogenesis is positioned as a viable contributor to febrile hypermetabolism, particularly during the maintenance phase. Febrile responses persist in UCP1-deficient models, while UCP3 disruption blunts LPS-induced hyperthermia, consistent with a muscle-linked contribution to febrile thermogenesis. Given that UCP3 is generally viewed as a metabolic-support uncoupler rather than a dedicated adaptive heat generator, sarcolipin-mediated SERCA uncoupling emerges as a plausible, scalable alternative. Inflammatory challenges are associated with increased muscle SLN expression without parallel SERCA expansion. These observations motivate integrated calorimetry, electromyography, and tissue-specific perturbation approaches to quantify skeletal muscle heat production during fever and distinguish putative SERCA uncoupling from shivering across translational models.