STIM1 R304W causes muscle degeneration and impaired platelet activation in mice. (December 2018)

• Record Type: Journal Article
• Authors: Gamage, Thilini H.; Gunnes, Gjermund; Lee, Robert Hugh; Louch, William Edward; Holmgren, Asbjørn; Bruton, Joseph D.; Lengle, Emma; Kolstad, Terje R. Selnes; Revold, Tobias; Amundsen, Silja Svanstrøm; Dalen, Knut Tomas; Holme, Pål Andre; Tjønnfjord, Geir Erland; Christensen, Geir; Westerblad, Håkan; Klungland, Arne; Bergmeier, Wolfgang; Misceo, Doriana; Frengen, Eirik
• Is Part Of: Cell calcium. Volume 76(2018)
• Page Start: 87
• Page End: 100
• Publication Date: 2018-12
• Subjects: Stim1 R304W -- Muscle degeneration -- Stormorken syndrome -- Stim1 expression -- Platelet dysfunction; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2018.10.001
• Languages: English
• ISSNs: 0143-4160

Abstract

Graphical abstract: Highlights: The Stormorken syndrome causing mutation in STIM1 (R304W) causes perinatal lethality in homozygous mice. Stim1 R304W mice show muscle degeneration and reduced growth. The STIM1 R304W gain-of-function is counteracted by reduced STIM1 expression in fibroblasts from Stim1 R304W mice. STIM1 loss in haematopoietic cells similarly causes absent SOCE and impaired platelet activation in Stim1 R304W mice. Unlike humans, mice compensate for constitutive activity of Stim1 R304W by reduced expression of the mutant allele. Abstract: STIM1 and ORAI1 regulate store-operated Ca 2+ entry (SOCE) in most cell types, and mutations in these proteins have deleterious and diverse effects. We established a mouse line expressing the STIM1 R304 W gain-of-function mutation causing Stormorken syndrome to explore effects on organ and cell physiology. While STIM1 R304 W was lethal in the homozygous state, surviving mice presented with reduced growth, skeletal muscle degeneration, and reduced exercise endurance. Variable STIM1 expression levels between tissues directly impacted cellular SOCE capacity. In contrast to patients with Stormorken syndrome, STIM1 was downregulated in fibroblasts from Stim1 R304W/R304W mice, which maintained SOCE despite constitutive protein activity. In studies using foetal liver chimeras, STIM1 protein was undetectable in homozygous megakaryocytes and platelets, resulting in impaired platelet activation and absent SOCE. These data indicate that downregulation of STIM1 R304 W effectively opposes the gain-of-function phenotype associated with this mutation, and highlight the importance of STIM1 in skeletal muscle development and integrity.