Disruption of STIM1-mediated Ca<sup>2+</sup> sensing and energy metabolism in adult skeletal muscle compromises exercise tolerance, proteostasis, and lean mass.



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.





Published Version (Please cite this version)


Publication Info

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

Associate Professor in Medicine

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

Assistant Professor in Medicine

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.


Paul Brian Rosenberg

Professor of Medicine

Deborah Marie Muoio

George Barth Geller Distinguished Professor of Cardiovascular Disease

Deb Muoio is professor in the Departments of Medicine and Pharmacology & Cancer Biology, George Barth Geller Distinguished Professor of Cardiovascular Disease, and Associate Director of the Duke Molecular Physiology Institute (DMPI). She is viewed nationally and internationally as a leader in the fields of diabetes, obesity, exercise physiology, and mitochondrial energy metabolism. Her laboratory investigates mechanisms of metabolic regulation, with emphasis on molecular events that link lifestyle factors such as over nutrition and physical inactivity to metabolic disorders, including obesity, diabetes, and heart failure. Her program features a translational approach that combines work in animal and cell-based models with human studies, using genetic engineering, molecular biology and mass spectrometry-based metabolomics and proteomics as tools to understand the interplay between mitochondrial physiology and cardiometabolic health. Her laboratory developed a sophisticated platform for deep and comprehensive assessment of mitochondrial bioenergetics and energy transduction. Her team is integrating this new platform with metabolomics, proteomics, and metabolic flux analysis to gain insights into mechanisms by which mitochondria modulate insulin action and metabolic resilience. She has published more than 120 papers in prominent journals such as Cell, Cell Metabolism, Circulation, Circulation Research, Diabetes, and JCI Insight. Dr. Muoio’s laboratory has enjoyed longstanding support from the NIDDK and NHLBI.

PhD, University of North Carolina, Chapel Hill, NC

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