: Intracellular calcium (Ca²⁺) homeostasis plays a vital role in the preservation of skeletal muscle. In view of the well-maintained skeletal muscle found in Daurian ground squirrels (Spermophilus dauricus) during hibernation, we hypothesized that hibernators possess unique strategies of intracellular Ca²⁺ homeostasis. Here, cytoplasmic, sarcoplasmic reticulum (SR), and mitochondrial Ca²⁺ levels, as well as the potential Ca²⁺ regulatory mechanisms, were investigated in skeletal muscle fibers of Daurian ground squirrels at different stages of hibernation. The results showed that cytoplasmic Ca²⁺ levels increased in the skeletal muscle fibers during late torpor (LT) and inter-bout arousal (IBA), and partially recovered when the animals re-entered torpor (early torpor, ET). Furthermore, compared with levels in the summer active or pre-hibernation state, the activity and protein expression levels of six major Ca²⁺ channels/proteins were up-regulated during hibernation, including the store-operated Ca²⁺ entry (SOCE), ryanodine receptor 1 (RyR1), leucine zipper-EF-hand containing transmembrane protein 1 (LETM1), SR Ca²⁺ ATPase 1 (SERCA1), mitochondrial calcium uniporter complex (MCU complex), and calmodulin (CALM). Among these, the increased extracellular Ca²⁺ influx mediated by SOCE, SR Ca²⁺ release mediated by RyR1, and mitochondrial Ca²⁺ extrusion mediated by LETM1 may be triggers for the periodic elevation in cytoplasmic Ca²⁺ levels observed during hibernation. Furthermore, the increased SR Ca²⁺ uptake through SERCA1, mitochondrial Ca²⁺ uptake induced by MCU, and elevated free Ca²⁺ binding capacity mediated by CALM may be vital strategies in hibernating ground squirrels to attenuate cytoplasmic Ca²⁺ levels and restore Ca²⁺ homeostasis during hibernation. Compared with that in LT or IBA, the decreased extracellular Ca²⁺ influx mediated by SOCE and elevated mitochondrial Ca²⁺ uptake induced by MCU may be important mechanisms for the partial cytoplasmic Ca²⁺ recovery in ET. Overall, under extreme conditions, hibernating ground squirrels still possess the ability to maintain intracellular Ca²⁺ homeostasis.

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