Disruption of STIM1-mediated Ca2+ sensing and energy metabolism in adult skeletal muscle compromises exercise tolerance, proteostasis, and lean mass.

Rebecca J Wilson, Scott P Lyons, Timothy R Koves, Victoria G Bryson, Hengtao Zhang, TianYu Li, Scott B Crown, Jin-Dong Ding, Paul A Grimsrud, Paul B Rosenberg, Deborah M Muoio

Molecular metabolism 2022 Mar

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Stromal interaction molecule 1 (STIM1) is a single-pass transmembrane endoplasmic/sarcoplasmic reticulum (E/SR) protein recognized for its role in a store operated Ca2+ entry (SOCE), an ancient and ubiquitous signaling pathway. Whereas STIM1 is known to be indispensable during development, its biological and metabolic functions in mature muscles remain unclear. Conditional and tamoxifen inducible muscle STIM1 knock-out mouse models were coupled with multi-omics tools and comprehensive physiology to understand the role of STIM1 in regulating SOCE, mitochondrial quality and bioenergetics, and whole-body energy homeostasis. This study shows that STIM1 is abundant in adult skeletal muscle, upregulated by exercise, and is present at SR-mitochondria interfaces. Inducible tissue-specific deletion of STIM1 (iSTIM1 KO) in adult muscle led to diminished lean mass, reduced exercise capacity, and perturbed fuel selection in the settings of energetic stress, without affecting whole-body glucose tolerance. Proteomics and phospho-proteomics analyses of iSTIM1 KO muscles revealed molecular signatures of low-grade E/SR stress and broad activation of processes and signaling networks involved in proteostasis. These results show that STIM1 regulates cellular and mitochondrial Ca2+ dynamics, energy metabolism and proteostasis in adult skeletal muscles. Furthermore, these findings provide insight into the pathophysiology of muscle diseases linked to disturbances in STIM1-dependent Ca2+ handling. Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.

Citation

Rebecca J Wilson, Scott P Lyons, Timothy R Koves, Victoria G Bryson, Hengtao Zhang, TianYu Li, Scott B Crown, Jin-Dong Ding, Paul A Grimsrud, Paul B Rosenberg, Deborah M Muoio. Disruption of STIM1-mediated Ca2+ sensing and energy metabolism in adult skeletal muscle compromises exercise tolerance, proteostasis, and lean mass. Molecular metabolism. 2022 Mar;57:101429