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

Abstract

AbstractStromal 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 focus on a gain of function mutation that occurs in humans and mice (STIM1+/D84Gmice) where muscles exhibit 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+/D84Gmuscle 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 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.