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

Stromal interaction molecule 1 (STIM1) is a Ca ²⁺ sensor located in the sarcoplasmic reticulum (SR) of skeletal muscle where it is best known for its role in store operated Ca ²⁺ entry (SOCE). Genetic syndromes resulting from STIM1 mutations are recognized as a cause of muscle weakness and atrophy. Here, we focus on a gain of function mutation that occurs in humans and mice (STIM1 ^+/D84G mice) where muscles exhibit constitutive SOCE. Unexpectedly, this constitutive SOCE did not affect global Ca ²⁺ transients, SR Ca ²⁺ 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 disrupts nuclear-cytosolic coupling causing severe derangement in nuclear architecture, DNA damage, and altered lamina A associated gene expression. Functionally, we found D84G STIM1 reduced the transfer of Ca ²⁺ from the cytosol to the nucleus in myoblasts resulting in a reduction of [Ca ²⁺ ] _N . Taken together, we propose a novel role for STIM1 in the nuclear envelope that links Ca ²⁺ signaling to nuclear stability in skeletal muscle.