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Recent interest has focused on the importance of the nucleus and associated nucleoskeleton in regulating changes in cardiac gene expression in response to biomechanical load. Mutations in genes encoding proteins of the inner nuclear membrane and nucleoskeleton, which cause cardiomyopathy, also disrupt expression of a biomechanically responsive gene program. Furthermore, mutations in the outer nuclear membrane protein Nesprin 1 and 2 have been implicated in cardiomyopathy. Here, we identify for the first time a role for the outer nuclear membrane proteins, Nesprin 1 and Nesprin 2, in regulating gene expression in response to biomechanical load. Ablation of both Nesprin 1 and 2 in cardiomyocytes, but neither alone, resulted in early onset cardiomyopathy. Mutant cardiomyocytes exhibited altered nuclear positioning, shape, and chromatin positioning. Loss of Nesprin 1 or 2, or both, led to impairment of gene expression changes in response to biomechanical stimuli. These data suggest a model whereby biomechanical signals are communicated from proteins of the outer nuclear membrane, to the inner nuclear membrane and nucleoskeleton, to result in changes in gene expression required for adaptation of the cardiomyocyte to changes in biomechanical load, and give insights into etiologies underlying cardiomyopathy consequent to mutations in Nesprin 1 and 2., Author Summary Cardiomyopathy is one of the major causes of heart failure, and the leading cause of mortality in the western world. A number of cardiomyopathies are caused by genetic mutations in structural proteins within the cardiomyocyte. Recent interest has turned to structural proteins that link the nucleoskeleton to the cytoskeleton (The LINC complex). Disruption of these factors cause both mechanical and gene response changes that cause varying degrees of pathology. In particular two genes, Nesprins 1 and 2 are of key interest as they share a high degree of homology and both have been found in Emery-Dreifuss muscular dystrophy (EDMD) patients with cardiomyopathy. Studies of these factors in the heart; however, have been limited due to early lethality of dual ablation of both Nesprins 1 and 2 in global knockout mice. Here, we examine targeted genetic ablation of Nesprin 1 and/or Nesprin 2 in a novel set of mouse lines. These studies found that loss of these factors caused early onset of cardiomyopathy, changes in nuclear position and morphology, as well as inhibition of the biomechanical gene response. Together, these data demonstrate that Nesprin 1 and 2 play critical and overlapping roles in the heart during homeostasis and pathology.