title: Enhanced Ca²⁺ influx from STIM1-Orai1 induces muscle pathology in mouse models of muscular dystrophy.
abstract: Muscular dystrophy is a progressive muscle wasting disease that is thought to be initiated by unregulated Ca(2+) influx into myofibers leading to their death. Store-operated Ca(2+) entry (SOCE) through sarcolemmal Ca(2+) selective Orai1 channels in complex with STIM1 in the sarcoplasmic reticulum is one such potential disease mechanism for pathologic Ca(2+) entry. Here, we generated a mouse model of STIM1 overexpression in skeletal muscle to determine whether this type of Ca(2+) entry could induce muscular dystrophy. Myofibers from muscle-specific STIM1 transgenic mice showed a significant increase in SOCE in skeletal muscle, modeling an observed increase in the same current in dystrophic myofibers. Histological and biochemical analysis of STIM1 transgenic mice showed fulminant muscle disease characterized by myofiber necrosis, swollen mitochondria, infiltration of inflammatory cells, enhanced interstitial fibrosis and elevated serum creatine kinase levels. This dystrophic-like disease in STIM1 transgenic mice was abrogated by crossing in a transgene expressing a dominant-negative Orai1 (dnOrai1) mutant. The dnOrai1 transgene also significantly reduced the severity of muscular dystrophy in both mdx (dystrophin mutant mice) and δ-sarcoglycan-deficient (Sgcd(-/-)) mouse models of disease. Hence, Ca(2+) influx across an unstable sarcolemma due to increased activity of a STIM1-Orai1 complex is a disease determinant in muscular dystrophy, and hence, SOCE represents a potential therapeutic target.
authors.affiliation: Department of Pediatrics, University of Cincinnati and.
authors.forename: Sanjeewa A
authors.initials: SA
authors.lastname: Goonasekera
authors.affiliation: Department of Pediatrics, University of Cincinnati and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Davis
authors.affiliation: Department of Pediatrics, University of Cincinnati and.
authors.forename: Jennifer Q
authors.initials: JQ
authors.lastname: Kwong
authors.affiliation: Department of Pediatrics, University of Cincinnati and.
authors.forename: Federica
authors.initials: F
authors.lastname: Accornero
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Wei-LaPierre
authors.affiliation: Department of Pediatrics, University of Cincinnati and.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Sargent
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dirksen
authors.affiliation: Department of Pediatrics, University of Cincinnati and Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA and jeff.molkentin@cchmc.org.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000378:metabolism / Q000473:pathology*; D009137:Muscular Dystrophy, Animal; D009363:Neoplasm Proteins / Q000378:metabolism*; D000071740:ORAI1 Protein; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C520430:Orai1 protein, mouse; C103530:STIM1 protein, human; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D002118:Calcium