Introduction Emery-Dreifuss muscular dystrophy (EDMD) is characterized by a triad of clinical symptoms: i/ a slowly progressive muscle weakness and wasting in a scapulo-humeroperoneal distribution; ii/ contractures of the elbows, ankles, and posterior neck; and iii/ a dilated cardiomyopathy associated with conduction defects. The autosomal forms of EDMD are caused by mutations in LMNA, encoding nuclear A-type lamins. It is still not clear how LMNA mutations cause alterations of skeletal and cardiac muscles, given that A-type lamins are ubiquitously expressed, Hypothesis To gain insight in the pathogenesis of striated muscle in EDMD, we studied the homozygote knock-in KI-Lmnap.H222P mice carrying a mutation previously found in patients (Bonne, 2000). Results We showed that slow-twitch soleus muscles from KI-Lmnap.H222P mice displayed a significant reduction (50%) of tension compared to control mice at 6 months of age. To identify abnormal expression of genes involved in development of muscular dystrophy, we next carried out a genome-wide RNA expression analysis in soleus from KI-Lmnap.H222P mice. Soleus muscles were isolated at 2 (pre-symptomatic) and 6 (symptomatic) months of age and transcription profiles determined using amplified RNA for Affymetrix array analyses. Hierchical cluster analysis identified distinct patterns of gene expression for each group of mice. We next used a supervised learning method to distinguish probe sets representing genes with significant differences in expression between soleus from control and mutant mice. Probe sets were selected using sufficiently high absolute changes measured by p values (p < 0.05) and expression was more than 2-fold different from control. This analysis yielded 204 probe sets in soleus from KI-Lmnap.H222P mice from 2 to 6 months of age. The 204 probe sets identified corresponded to 172 upregulated genes and 32 downregulated. We used David software, which analyses gene ontology terms applied to genes, to identify functional classes of genes differentially expressed in soleus of KI-Lmnap.H222P mice from 4 to 6 months of age. The highest scoring gene ontology classes were genes encoding proteins involved in skeletal muscle cell differentiation, myofibril and actin cytoskeleton. Conclusion We here identified alterations of canonical pathways, which are involved in the EDMD skeletal muscle pathogenesis. The dissection of these alterations will shed light on the pathogenesis of the diseases and will potentially identify new therapeutic targets.