title: Orai1 enhances muscle endurance by promoting fatigue-resistant type I fiber content but not through acute store-operated Ca2+ entry.
abstract: Orai1 is a transmembrane protein that forms homomeric, calcium-selective channels activated by stromal interaction molecule 1 (STIM1) after depletion of intracellular calcium stores. In adult skeletal muscle, depletion of sarcoplasmic reticulum calcium activates STIM1/Orai1-dependent store-operated calcium entry. Here, we used constitutive and inducible muscle-specific Orai1-knockout (KO) mice to determine the acute and long-term developmental effects of Orai1 ablation on muscle structure and function. Skeletal muscles from constitutive, muscle-specific Orai-KO mice exhibited normal postnatal growth and fiber type differentiation. However, a significant reduction in fiber cross-sectional area occurred by 3 mo of age, with the most profound reduction observed in oxidative, fatigue-resistant fiber types. Soleus muscles of constitutive Orai-KO mice exhibited a reduction in unique type I fibers, concomitant with an increase in hybrid fibers expressing both type I and type IIA myosins. Additionally, ex vivo force measurements showed reduced maximal specific force and in vivo exercise assays revealed reduced endurance in constitutive muscle-specific Orai-KO mice. Using tamoxifen-inducible, muscle-specific Orai-KO mice, these functional deficits were found to be the result of the delayed fiber changes resulting from an early developmental loss of Orai1 and not the result of an acute loss of Orai1-dependent store-operated calcium entry.-Carrell, E. M., Coppola, A. R., McBride, H. J., Dirksen, R. T. Orai1 enhances muscle endurance by promoting fatigue-resistant type I fiber content but not through acute store-operated Ca2+entry.
authors: Department of Physiology and Pharmacology, University of Rochester, Rochester, New York, USA; and.
authors: Ellie M
authors: EM
authors: Carrell
authors: Department of Inflammation Research, Amgen Incorporated, Thousand Oaks, California, USA.
authors: Aundrea R
authors: AR
authors: Coppola
authors: Department of Inflammation Research, Amgen Incorporated, Thousand Oaks, California, USA.
authors: Helen J
authors: HJ
authors: McBride
authors: Department of Physiology and Pharmacology, University of Rochester, Rochester, New York, USA; and robert_dirksen@urmc.rochester.edu.
authors: Robert T
authors: RT
authors: Dirksen
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics; D000071740:ORAI1 Protein / Q000235:genetics*; D000071737:Stromal Interaction Molecule 1 / Q000235:genetics
chemical_list: D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002118:Calcium
keywords: development; exercise; myosin; skeletal muscle