Disruption of STIM1-mediated Ca<sup>2+</sup> sensing and energy metabolism in adult skeletal muscle compromises exercise tolerance, proteostasis, and lean mass.
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2022-03
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Abstract
Objective
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.Methods
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.Results
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.Conclusion
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.Type
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Wilson, Rebecca J, Scott P Lyons, Timothy R Koves, Victoria G Bryson, Hengtao Zhang, TianYu Li, Scott B Crown, Jin-Dong Ding, et al. (2022). Disruption of STIM1-mediated Ca2+ sensing and energy metabolism in adult skeletal muscle compromises exercise tolerance, proteostasis, and lean mass. Molecular metabolism, 57. p. 101429. 10.1016/j.molmet.2021.101429 Retrieved from https://hdl.handle.net/10161/30114.
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Timothy Robert Koves
My research is focused on 1) understanding metabolic perturbations that occur in subpopulations of skeletal muscle mitochondria in response to a chronic high lipid environment, 2) identifying specific metabolites of lipid-induced mitochondrial stress that contribute to skeletal muscle insulin resistance and type II diabetes, and 3) understanding how mitochondrial adaptations in response to exercise confer protection against lipid-induced mitochondrial dysfunction.
Paul Grimsrud
Paul Grimsrud is an Assistant professor of Medicine—in the Division of Endocrinology, Metabolism, and Nutrition—and Proteomics Section Leader at the Duke Molecular Physiology Institute. He completed a PhD in Biochemistry at the University of Minnesota-Twin Cities and a postdoctoral fellowship at the University of Wisconsin-Madison. His research combines mass spectrometry-based proteomics with complementary biochemical approaches to characterize the regulation of metabolism and signaling by protein post-translational modifications (PTMs). He is particularly interested in mechanisms that link altered mitochondrial function to metabolic diseases, such as heart failure, type 2 diabetes, and cancer. He works with colleagues to apply quantitative PTM measurements to relevant model systems, leverage bioinformatics tools to develop testable hypotheses from large-scale data, and characterize mechanisms of PTM-mediated metabolic control.
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