Investigating the effects of thermoneutral housing on skeletal muscle SERCA efficiency in mice fed a high-fat diet with and without exercise training

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Thermoneutral (TN) housing of mice is an important factor to better mimic human metabolism and optimize translational research. The sarco(endo)plasmic reticulum (SR) Ca2+ ATPase (SERCA) pump actively transports Ca2+ from the cytosol into the SR, making it a regulator of muscle relaxation and energy metabolism. In response to cold or caloric excess, SERCA inefficiency generates heat and drives the combustion of metabolic substrates in muscle; however, whether TN housing affects SERCA efficiency is unknown. Here, we determined SERCA pump efficiency in skeletal muscles of mice housed at room temperature (RT, 22°C) or TN (30°C) with and without 60%E high-fat diet (HFD) and exercise training (ET) interventions. We hypothesize that TN would increase SERCA efficiency compared to RT on a chow diet, and that HFD and HFD + ET would reduce SERCA efficiency at both housing temperatures. Mice housed at RT or TN were fed a chow or 60%E HFD for 16 weeks. Eight weeks into the diet, half of the mice on HFD were randomly assigned to either ET or remained sedentary (SED) for the remaining 8 weeks. HFD + ET increased SERCA’s affinity for Ca2+ and maximal SERCA activity trended reduced by ET compared to HFD + SED mice. Investigating SERCA efficiency at low physiological [Ca2+]free shows that TN reduced Ca2+ uptake by ~60% in HFD mice and reduced SERCA activity by ~60% in SED mice. This increased SERCA efficiency 4-fold in chow-fed mice housed at TN compared to RT and reduced SERCA efficiency in HFD mice at TN to ~80% of that of chow-fed mice at TN. Similarly, at high physiological [Ca2+]free, TN reduced Ca2+ uptake by ~40% in HFD mice and reduced SERCA activity by ~35% in SED mice, but had no effect on SERCA efficiency. Together, TN housing appears to influence SERCA efficiency especially under chow and HFD conditions at a low [Ca2+]free. In conclusion, housing mice at TN should be considered when investigating non-shivering thermogenic mechanisms and skeletal muscle Ca2+ handling. Jessica L. Braun and Steffen H. Raun contributed equally. Erik A. Richter and Lykke Sylow are co-corresponding authors. Disclosure of funding: JLB. is supported by a Canadian Institute for Health Research Doctoral grant and a Michael Smith Foreign Study Supplement. SHR is supported by the Lundbeck Foundation and the Independent Research Fund Denmark. LS is supported by the Novo Nordisk Foundation and Independent Research Fund Denmark. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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