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Nonshivering thermogenesis protects against defective calcium handling in muscle

Jan Aydin^*, Irina G. Shabalina, Nicolas Place^*, Steven Reiken, Shi-Jin Zhang^*, Andrew M. Bellinger, Jan Nedergaard, Barbara Cannon, Andrew R. Marks, Joseph D. Bruton^* and Håkan Westerblad^*,1

^* Department of Physiology and Pharmacology, Karolinska Institutet, and

The Wenner-Gren Institute, The Arrhenius Laboratories, Stockholm, Sweden; and

Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, New York, New York, USA

¹ Correspondence: Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden. E-mail: hakan.westerblad{at}ki.se

When acutely exposed to a cold environment, mammals shiver to generate heat. During prolonged cold exposure, shivering is replaced by adaptive adrenergic nonshivering thermogenesis with increased heat production in brown adipose tissue due to activation of uncoupling protein-1 (UCP1). This cold acclimation is associated with chronically increased sympathetic stimulation of skeletal muscle, which may increase the sarcoplasmic reticulum (SR) Ca²⁺ leak via destabilized ryanodine receptor 1 (RyR1) channel complexes. Here, we use genetically engineered UCP1-deficient (UCP1-KO) mice that rely completely on shivering in the cold. We examine soleus muscle, which participates in shivering, and flexor digitorum brevis (FDB) muscle, a distal and superficial muscle that does not shiver. Soleus muscles of cold-acclimated UCP1-KO mice exhibited severe RyR1 PKA hyperphosphorylation and calstabin1 depletion, as well as markedly decreased SR Ca²⁺ release and force during contractions. In stark contrast, the RyR1 channel complexes were little affected, and Ca²⁺ and force were not decreased in FDB muscles of cold-acclimated UCP1-KO mice. These results indicate that activation of UCP1-mediated heat production in brown adipose tissue during cold exposure reduces the necessity for shivering and thus prevents the development of severe dysfunction in shivering muscles. Aydin, J., Shabalina, I. G., Place, N., Reiken, S., Zhang, S.-J., Bellinger, A. M., Nedergaard, J., Cannon, B., Marks, A. R., Bruton, J. D., Westerblad, H. Nonshivering thermogenesis protects against defective calcium handling in muscle.

Key Words: muscle contraction • ryanodine receptor • temperature control • increased β-adrenergic activity