Dystrophin muscle enhancer 1 is implicated in the activation of non-muscleisoforms in the skeletal muscle of patients with X-linked dilated cardiomyopathy

X-linked dilated cardiomyopathy (XLDC) is a dystrophinopathy characterized by severe cardiomyopathy with no skeletal muscle involvement. Several XLDC patients have been described with mutations that abolish dystrophin muscle (M) isoform expression. The absence of skeletal muscle degeneration normall y associated with loss of dystrophin function was shown to be due to increa sed expression of brain (B) and cerebellar Purkinje (CP) isoforms of the ge ne exclusively in the skeletal muscle of these patients. This suggested tha t the B and CP promoters have an inherent capacity to function in skeletal muscle or that they are up-regulated by a skeletal muscle-specific enhancer unaffected by the mutations in these patients. In this work we have analyz ed the deletion breakpoints of two XLDC patients with deletions removing th e M promoter and exon 1, but not affecting the B and CP promoters. Despite the presence of several muscle-specific regulatory motifs, the B and CP pro moters were found to be essentially inactive in muscle cell lines and prima ry cultures. As dystrophin muscle enhancer 1 (DME1), the only known muscle- specific enhancer within the dystrophin gene, is preserved in these patient s, we tested its ability to up-regulate the B and CP promoters in muscle ce lls. B and CP promoter activity was significantly increased in the presence of DME1, and more importantly, activation was observed exclusively in cell s presenting a skeletal muscle phenotype. These results point to a role for DME1 in the induction of B and CP isoform expression in the skeletal muscl e of XLDC patients defective for M isoform expression.