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Mutations in the lamin A/C gene ( LMNA ) encoding A-type nuclear lamins cause dilated cardiomyopathy with variable muscular dystrophy. These mutations enhance mitogen-activated protein kinase signaling in the heart and pharmacological inhibition of extracellular signal-regulated kinase (ERK) 1 and 2 improves cardiac function in  Lmna  H222P/H222P  mice. In the current study, we crossed mice lacking ERK1 to  Lmna  H222P/H222P  mice and examined cardiac performance and survival. Male  Lmna  H222P/H222P / Erk1  −/−  mice lacking ERK1 had smaller left ventricular end systolic diameters and increased fractional shortening (FS) at 16 weeks of age than  Lmna  H222P/H222P/  Erk1  +/+  mice. Their mean survival was also significantly longer. However, the improved cardiac function was abrogated at 20 weeks of age concurrent with an increased activity of ERK2.  Lmna  H222P/H222P / Erk1  −/−  mice treated with an inhibitor of ERK1/2 activation had smaller left ventricular diameters and increased FS at 20 weeks of age. These results provide genetic evidence that ERK1 and ERK2 contribute to the development of cardiomyopathy caused by  LMNA  mutations and reveal interplay between these isoenzymes in maintaining a combined pathological activity in heart.

human molecular genetics

Depletion of extracellular signal-regulated kinase 1 in mice with cardiomyopathy caused by lamin A/C gene mutation partially prevents pathology before isoenzyme activation