Alternative utrophin mRNAs contribute to phenotypic differences between dystrophin‐deficient mice and Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a fatal disorder caused by absence of functional dystrophin protein. Compensation in dystrophin‐deficient (mdx) mice may be achieved by overexpression of its fetal paralogue, utrophin. Strategies to increase utrophin levels by stimulating promoter activity using small compounds are therefore a promising pharmacological approach. Here, we characterise similarities and differences existing within the mouse and human utrophin locus to assist in high‐throughput screening for potential utrophin modulator drugs. We identified five novel 5′‐utrophin isoforms (A′,B′,C,D and F) in adult and embryonic tissue. As the more efficient utrophin‐based response in mdx skeletal muscle appears to involve independent transcriptional activation of conserved, myogenic isoforms (A′ and F), elevating their paralogues in DMD patients is an encouraging therapeutic strategy.

Noncoding RNAs in Duchenne and Becker muscular dystrophies: role in pathogenesis and future prognostic and therapeutic perspectives

“…Utrophin is a protein analogue to dystrophin, able to partially compensate in its absence. This compensatory mechanism differs in mice and humans, due to differential regulation of Utrn isoforms, and provide a major protective effect in mdx mouse model, responsible for the milder phenotype compared to DMD patients [154]. Utrophin expression can be downregulated by miR-206, miR-150, miR-196b, miR-296-5p, miR-133b and let-7c; blocking those miRNAs resulted in increased levels of utrophin in C2C12 cells [155].…”

Endogenous bioluminescent reporters reveal a sustained increase in utrophin gene expression upon EZH2 and ERK1/2 inhibition

“…Although dystrophin is the predominant paralogue expressed in adult skeletal muscle, utrophin is expressed earlier in development 27 , 30 , 48 . To monitor the expression of both paralogues during mouse ontogeny, we performed bioluminescent imaging and molecular analyses using heterozygote embryos generated by crossing Dmd G and Utrn R reporter lines.…”

“…In skeletal muscle, utrophin is expressed throughout the sarcolemma during foetal and perinatal development, but becomes restricted to neuromuscular and myotendinous junctions postnatally, while dystrophin occupies the sarcolemma 27 – 29 . Detailed analyses of utrophin gene structure revealed at least two promoters (A and B) that generate different isoforms with distinct expression patterns 30 – 32 . Since utrophin-A promoter activity correlates most closely with dystrophin expression, much attention has been focused on defining strategies and screening for compounds that enhance Utrn expression via increased Utrn-A promoter activity.…”

Therapeutic Implications of miRNAs for Muscle-Wasting Conditions

“…The restoration of miR-29 in mdx mice has been shown to improve the pathology of dystrophy by promoting the regeneration of muscle tissue and decreasing fibrosis [ 81 ]. Furthermore, the coupled administration of micro-dystrophin and miR-29 has been shown to restore muscle strength in mdx mice [ 82 ].…”