The D84G mutation in STIM1 causes nuclear envelope dysfunction and myopathy in mice
Victoria Bryson, … , Eda Yildirim, Paul Rosenberg
Victoria Bryson, … , Eda Yildirim, Paul Rosenberg
Published February 1, 2024
Citation Information: J Clin Invest. 2024;134(7):e170317. https://doi.org/10.1172/JCI170317.
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Research Article Cell biology Muscle biology

The D84G mutation in STIM1 causes nuclear envelope dysfunction and myopathy in mice

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.

Authors

Victoria Bryson, Chaojian Wang, Zirui Zhou, Kavisha Singh, Noah Volin, Eda Yildirim, Paul Rosenberg

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Figure 3

Ca2+ signaling in D84G-mutant mice.

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Ca2+ signaling in D84G-mutant mice. (A–C) Manganese (Mn2+) quench assays...
(A–C) Manganese (Mn2+) quench assays were performed on Fura-2–loaded FDB fibers to quantitate SOCE expression in WT and STIM1+/D84G mice (n = 3 male mice; n = 30 fibers) (A) Spontaneous and EFS Mn2+ quench rate in WT and STIM1+/D84G fibers. (B) Spontaneous Mn2+ quench rate was significantly increased in STIM1+/D84G mice (P > 0.05). (C) The Mn2+ quench following electrical field stimulation (EFS) was not significantly different. (D) Basal Ca2+ levels measured by the Fura-2 method were not different between WT and STIM1+/D84G fibers. (E and F) Ca2+ release evoked by caffeine from Fura-4F–loaded FDB fibers (E). The AUC (F) did not differ between WT and STIM1+/D84G fibers (n = 3 mice; n = 30 fibers per genotype). (G) EFS Ca2+ transients from Fura-4F–loaded FDB muscle fibers were similar (n = 4 mice; n = 50 fibers per genotype). (H and I) Graphical representation of peak amplitude and frequency (H) shows no significant changes in peak Ca2+ release per EFS (I) but a significant elevation in interstimulus Ca2+ from STIM1+/D84G fibers (n = 3 mice; n = 50 fibers per genotype). (J and K) Western blot analyses of Ca2+ handling proteins in 6-month-old WT and STIM1+/D84G mice (n = 5 per genotype). Lysates from GST muscles were prepared from WT and STIM1+/D84G mice. Antibodies for STIM1, RYR1, SERCA1, CASQ (top), and SLN (bottom) were used to quantify protein expression (Exp) versus GAPDH. Values are the mean ± SD. n ≥4 independent experiments. *P < 0.05, **P < 0.01, and ****P < 0.0001, by 2-tailed Student’s t test (NS, P > 0.05).