Thyroid hormone increases the Ca²⁺-ATPase activity of the sarcoplasmic reticulum (SR) in skeletal muscle, thereby increasing the energy-turnover associated with Ca²⁺-cycling during contraction and rest. The fast-muscle isoform of the Ca²⁺-ATPase (SERCA1) and the slow-muscle isoform (SERCA2a), are encoded by two genes that are transcriptionally regulated by T₃. The SERCA1 isoform can be expressed to considerably higher levels than the SERCA2a isoform. The stimulation of transcription of the SERCA1 gene by T₃ is mediated by two thyroid hormone response elements, located in the promoter of this gene. The intracellular [Ca²⁺] can modulate the effect of T₃. The increase in SR Ca²⁺-ATPase activity seen when T₃-levels rise above normal, results from the induction of SERCA1 expression in slow muscle fibers. Concomitant high levels of Ca²⁺-ATPase activity are associated with down-regulation of SERCA2a expression in these fibers. The observed T₃-dependent increase in SERCA1 expression and associated Ca²⁺-ATPase activity will increase the overall metabolic rate of the organism significantly under normal conditions, because of the high average level of contractile activity of slow fibers. Given the rise in serum T₃-levels during prolonged cold exposure, these data suggest that fiber-specific stimulation of SERCA1 expression contributes to the thermogenic response in non-shivering thermogenesis. This mechanism may be particularly relevant in larger mammals, which have a relatively high percentage of slow fibers in skeletal muscle, and which need to rely on tissues other than brown fat for the generation of extra heat.