Search

Aims Mutations in A-type nuclear lamins gene, LMNA, lead to a dilated cardiomyopathy. We have reported abnormal activation of the extracellular signal-regulated kinase1/2 (ERK1/2) signalling in hearts from LmnaH222P/H222P mice, which develop dilated cardiomyopathy. We therefore determined whether an inhibitor of ERK1/2 signalling that has been investigated in clinical trials for cancer has the potential to be translated to humans with LMNA cardiomyopathy. Methods and results To evaluate the relevance of this finding in mice to patients, we analysed the ERK1/2 signalling in heart tissue from human subjects with LMNA cardiomyopathy and showed that it was abnormally activated. To determine whether pharmacological inhibitors of the ERK1/2 signalling pathway could potentially be used to treat LMNA cardiomyopathy, we administered selumetinib to male LmnaH222P/H222P mice starting at 16 weeks of age, after they show signs of cardiac deterioration, up to 20 weeks of age. Selumetinib is an inhibitor of ERK1/2 signalling and has been given safely to human subjects in clinical trials for cancer. Systemic treatment with selumetinib inhibited cardiac ERK1/2 phosphorylation and blocked increased expression of RNAs encoding natriuretic peptide precursors and proteins involved in sarcomere architecture that occurred in placebo-treated mice. Echocardiography and histological analysis demonstrated that treatment increases cardiac fractional shortening, prevents myocardial fibrosis, and prolongs survival. Selumetinib treatment did not induce biochemical abnormalities suggestive of renal or hepatic toxicity. Conclusion Our results suggest that selumetinib or other related inhibitors that have been safely administered to humans in clinical trials could potentially be used to treat LMNA cardiomyopathy. [ABSTRACT FROM PUBLISHER]

Studies whether an autosomal dominantly inherited limb girdle muscular dystrophy (LGMD1B) and the autosomal dominant form of Emery-Dreifuss muscular dystrophy are allelic disorders by searching for mutations in LMNA gene of LGMD1B patients. Polymerase chain reaction/single strand conformation polymorphism/sequencing screening; Missense mutation; Deletion of colon; Splice donor site mutation.