Specifically, we show that mice harboring a single nucleotide change in STIM1 (D84G) displayed (a) constitutive Ca2+ entry across the sarcolemma of muscle fibers, (b) reduced muscle mass and weakness consistent with sarcopenia, and (c) disruption of the NE resulting in altered nuclear architecture, gene expression, and DNA damage. Here, STIM1 is linked to sarcopenia.