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Stromal interaction molecule 1 (STIM1) is a [Ca.sup.2+] sensor located in the sarcoplasmic reticulum (SR) of skeletal muscle, where it is best known for its role in store-operated [Ca.sup.2+] 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.sup.+/D84G] mice), in which muscles exhibited constitutive SOCE. Unexpectedly, this constitutive SOCE did not affect global [Ca.sup.2+] transients, SR [Ca.sup.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.sup.+/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 [Ca.sup.2+] from the cytosol to the nucleus in myoblasts, resulting in a reduction of [[[Ca.sup.2+]].sub.N]. Taken together, we propose a novel role for STIM1 in the nuclear envelope that links [Ca.sup.2+] signaling to nuclear stability in skeletal muscle., Introduction Stromal interaction molecule 1 (STIM1) is a transmembrane protein located in the sarcoplasmic reticulum (SR) of skeletal muscle, where it senses [Ca.sup.2+] stores and activates Orai channels as part [...]