The D84G mutation in STIM1 causes nuclear envelope dysfunction and myopathy in mice.
J Clin Invest
; 134(7)2024 Feb 01.
Article
en En
| MEDLINE
| ID: mdl-38300705
ABSTRACT
Stromal interaction molecule 1 (STIM1) is a Ca2+ sensor located in the sarcoplasmic reticulum (SR) of skeletal muscle, where it is best known for its role in store-operated Ca2+ entry (SOCE). Genetic syndromes resulting from STIM1 mutations are recognized as a cause of muscle weakness and atrophy. Here, we focused on a gain-of-function mutation that occurs in humans and mice (STIM1+/D84G mice), in which muscles exhibited constitutive SOCE. Unexpectedly, this constitutive SOCE did not affect global Ca2+ transients, SR Ca2+ content, or excitation-contraction coupling (ECC) and was therefore unlikely to underlie the reduced muscle mass and weakness observed in these mice. Instead, we demonstrate that the presence of D84G STIM1 in the nuclear envelope of STIM1+/D84G muscle disrupted nuclear-cytosolic coupling, causing severe derangement in nuclear architecture, DNA damage, and altered lamina A-associated gene expression. Functionally, we found that D84G STIM1 reduced the transfer of Ca2+ from the cytosol to the nucleus in myoblasts, resulting in a reduction of [Ca2+]N. Taken together, we propose a novel role for STIM1 in the nuclear envelope that links Ca2+ signaling to nuclear stability in skeletal muscle.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Debilidad Muscular
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Molécula de Interacción Estromal 1
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Membrana Nuclear
Tipo de estudio:
Etiology_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
J Clin Invest
Año:
2024
Tipo del documento:
Article