Several murine models for EDMD have been generated; however, emerin-null (Emd) mice do not show obvious skeletal and cardiac muscle phenotypes, and Lmna H222P/H222P mutant (H222P) mice show only a mild phenotype in skeletal muscle when they already have severe cardiomyopathy.
We found that AKT-mechanistic target of rapamycin (MTOR) signaling was hyperactivated in hearts of Lmna (H222P/H222P) mice and that reducing MTOR activity by pharmacological intervention ameliorated cardiomyopathy.
Biochemical analysis of hearts from Lmna(H222P/H222P) mice showed enhanced p38α activation prior to and after the onset of heart disease as well as in hearts from human subjects with cardiomyopathy caused by LMNA mutations.
Dusp4 is highly expressed in the hearts of Lmna(H222P/H222P) mice, and transgenic mice with cardiac-selective overexpression of Dusp4 display heart dysfunction similar to LMNA cardiomyopathy.