PXD053472-1

PXD053472 is an original dataset announced via ProteomeXchange.

Title	Orai1 tubular aggregate myopathy mice exhibit compromised muscle function, mitochondrial alterations, and postnatal adaptations
Description	Tubular aggregate myopathy (TAM) is a heritable, myopathy primarily characterized by progressive muscle weakness, elevated levels of creatine kinase (CK), hypocalcemia, exercise intolerance, and the presence of tubular aggregates. Here, we generated a knock-in mouse model of TAM harboring a glycine-to-serine point mutation in the ORAI1 pore (Orai1G100S/+ or GS mice) that results in a severe, early-onset form of TAM in humans. By 8 months of age, OraiG100S/+ mice exhibit significant muscle weakness, exercise intolerance, elevated CK levels, hypocalcemia, and robust presence of tubular aggregates. Unexpectedly, constitutive Ca2+ entry due to the Orai1 pore mutation is only observed in muscle during early development and is abolished in adult skeletal muscle, due in part to a reduction in ORAI1 expression. Consistent with proteomic analysis of GS mice, we demonstrated a robust mitochondrial damage using both morphological and functional approaches. GS mice represent a powerful model to investigate the pathophysiological mechanisms that underlie the muscle weakness, exercise intolerance and formation of tubular aggregates, as well as compensatory responses to limit the damaging effects of uncontrolled ORAI1-mediated Ca2+ influx.
HostingRepository	PRIDE
AnnounceDate	2025-05-07
AnnouncementXML	Submission_2025-05-06_20:36:07.113.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	NAN ZHAO
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-27 21:36:16	ID requested
⏵ 1	2025-05-06 20:36:08	announced

10.1038/s44318-024-00273-4;

Zhao N, Michelucci A, Pietrangelo L, Malik S, Groom L, Leigh J, O'Connor TN, Takano T, Kingsley PD, Palis J, Boncompagni S, Protasi F, Dirksen RT, An Orai1 gain-of-function tubular aggregate myopathy mouse model phenocopies key features of the human disease. EMBO J, 43(23):5941-5971(2024) [pubmed]

submitter keyword: Tibialis Anterior Muscle, Mass Spectrometry, Tubuar Aggregate Myopathy,Mouse, SOCE, ORAI1, Skeletal Muscle

Robert T. Dirksen
contact affiliation	Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA
contact email	Robert_Dirksen@URMC.rochester.edu
lab head
NAN ZHAO
contact affiliation	University of Rochester
contact email	nan_zhao@urmc.rochester.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD053472
     1. Label: PRIDE project
     2. Name: Orai1 tubular aggregate myopathy mice exhibit compromised muscle function, mitochondrial alterations, and postnatal adaptations