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Junctophilin-2 (JP2) is a structural protein required for normal excitation-contraction (E-C) coupling. Following cardiac stress, JP2 is cleaved by Ca2+-dependent protease calpain, which disrupts the E-C coupling ultrastructural machinery and drives heart failure progression. Here we demonstrate that stress-induced proteolysis of JP2 liberates an N-terminal fragment (JP2NT) that translocates to the nucleus, binds to genomic DNA and controls expression of a spectrum of genes in cardiomyocytes. Transgenic overexpression of JP2NT in mice modifies the transcriptional profile resulting in attenuated pathological remodeling in response to cardiac stress. Conversely, loss of JP2NT function accelerates stress-induced development of hypertrophy and heart failure in mutant mice. These data reveal a self-protective mechanism in failing cardiomyocytes that transduce mechanical information (E-C uncoupling) into salutary transcriptional reprogramming in the stressed heart.