التفاصيل البيبلوغرافية
| العنوان: |
An Orai1 gain-of-function tubular aggregate myopathy mouse model phenocopies key features of the human disease. |
| المؤلفون: |
Zhao, Nan1 (AUTHOR), Michelucci, Antonio2 (AUTHOR), Pietrangelo, Laura3 (AUTHOR), Malik, Sundeep1 (AUTHOR), Groom, Linda1 (AUTHOR), Leigh, Jennifer1 (AUTHOR), O'Connor, Thomas N1 (AUTHOR), Takano, Takahiro1 (AUTHOR), Kingsley, Paul D4 (AUTHOR), Palis, James4 (AUTHOR), Boncompagni, Simona5 (AUTHOR), Protasi, Feliciano3 (AUTHOR), Dirksen, Robert T1 (AUTHOR) Robert_Dirksen@URMC.rochester.edu |
| المصدر: |
EMBO Journal. Dec2024, Vol. 43 Issue 23, p5941-5971. 31p. |
| مصطلحات موضوعية: |
*GAIN-of-function mutations, *CREATINE kinase, *MITOCHONDRIAL pathology, *CALCIUM channels, *SKELETAL muscle |
| مستخلص: |
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 (TAs). Here, we generated a knock-in mouse model based on a human gain-of-function mutation which results in a severe, early-onset form of TAM, by inducing a glycine-to-serine point mutation in the ORAI1 pore (Orai1G100S/+ or GS mice). By 8 months of age, GS mice exhibited significant muscle weakness, exercise intolerance, elevated CK levels, hypocalcemia, and robust TA presence. Unexpectedly, constitutive Ca2+ entry in mutant mice was observed in muscle only during early development and was abolished in adult skeletal muscle, partly due to reduced ORAI1 expression. Consistent with proteomic results, significant mitochondrial damage and dysfunction was observed in skeletal muscle of GS mice. Thus, GS mice represent a powerful model for investigation of the pathophysiological mechanisms that underlie key TAM symptoms, as well as those compensatory responses that limit the damaging effects of uncontrolled ORAI1-mediated Ca2+ influx. Synopsis: Tubular aggregate myopathy (TAM) is caused by mutations in ORAI1 and STIM1 subunits of the Ca2+-release-activated Ca2+ (CRAC) channel. This study found that mice with a gain-of-function mutation in the ORAI1 channel pore that results in TAM in humans (Orai1G100S/+ mice) possess multiple hallmarks of the human disease. Orai1G100S/+ mice exhibit a robust presence of tubular aggregates at 8 months of age. Orai1G100S/+ mice exhibit several additional features of TAM including muscle weakness, elevated creatine kinase (CK), hypocalcemia, and exercise intolerance. Initial enhanced constitutive Ca2+ entry observed during early development is abolished in muscle fibers from Orai1G100S/+ adult mice. Proteomic, morphological, and functional analyses reveal alterations in mitochondrial structure and function in skeletal muscle of adult Orai1G100S/+ mice. The human mutation in the Orai1 calcium channel responsible for tubular aggregate myopathy is transferred to create a mouse model that offers insight into the underlying pathological etiology. [ABSTRACT FROM AUTHOR] |
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