A-utrophin up-regulation in mdx skeletal muscle is independent of regeneration
Andrew P. Weir, Jennifer E. Morgan, Kay E. Davies
Abstract :
Duchenne
muscular dystrophy is a fatal childhood disease caused by mutations that
abolish the expression of dystrophin in muscle. Utrophin is a paralogue of
dystrophin and can functionally replace it in skeletal muscle. A method to
induce utrophin up-regulation in muscle should therefore be therapeutically
useful in Duchenne muscular dystrophy. The search for such a method needs to be
informed by an understanding of the mechanisms controlling utrophin expression
in muscle. Two full length utrophin isoforms are expressed: A and B. A-utrophin
is up-regulated in dystrophin deficient skeletal muscle and we sought to test
the hypothesis that this up-regulation occurs as a consequence of ongoing
regeneration. We measured utrophin expression by immunohistochemistry and
immunoblotting in the oesophageal outer muscular layer and in g-irradiated limb
muscle from mdx mice. Skeletal muscle in these tissues is dystrophin deficient
but not regenerating; we found that A-utrophin up-regulation still occurred. We
conclude that utrophin up-regulation in skeletal muscle does not depend on
regeneration. An alternative hypothesis involving competition for binding sites
between utrophin and dystrophin is discussed. These results have important
implications for future studies aiming to effect therapeutic utrophin
up-regulation in Duchenne muscular dystrophy patients.