Utrophin A is essential in mediating the functional adaptations of mdx mouse muscle following chronic AMPK activation.

Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin along muscle fibers. An attractive therapeutic avenue for DMD consists in the upregulation of utrophin A, a protein with high sequence identity and functional redundancy with dystrophin. Recent work has shown that pharmacological interventions that induce a muscle fiber shift toward a slower, more oxidative phenotype with increased expression of utrophin A confer morphological and functional improvements in mdx mice. Whether such improvements result from the increased expression of utrophin A per se or are linked to other beneficial adaptations associated with the slow, oxidative phenotype remain to be established. To address this central issue, we capitalized on the use of double knockout (dKO) mice, which are mdx mice also deficient in utrophin. We first compared expression of signaling molecules and markers of the slow, oxidative phenotype in muscles of mdx versus dKO mice and found that both strains exhibit similar phenotypes. Chronic activation of 5' adenosine monophosphate-activated protein kinase with 5-amino-4-imidazolecarboxamide riboside (AICAR) resulted in expression of a slower, more oxidative phenotype in both mdx and dKO mice. In mdx mice, this fiber type shift was accompanied by clear functional improvements that included reductions in central nucleation, IgM sarcoplasmic penetration and sarcolemmal damage resulting from eccentric contractions, as well as in increased grip strength. These important morphological and functional adaptations were not seen in AICAR-treated dKO mice. Our findings show the central role of utrophin A in mediating the functional benefits associated with expression of a slower, more oxidative phenotype in dystrophic animals.

Al-Rewashdy H ，Ljubicic V ，Lin W ，Renaud JM ，Jasmin BJ ... -  《-》

Chronic AMPK activation evokes the slow, oxidative myogenic program and triggers beneficial adaptations in mdx mouse skeletal muscle.

Ljubicic V ，Miura P ，Burt M ，Boudreault L ，Khogali S ，Lunde JA ，Renaud JM ，Jasmin BJ ... -  《-》

Pharmacological activation of PPARbeta/delta stimulates utrophin A expression in skeletal muscle fibers and restores sarcolemmal integrity in mature mdx mice.

Miura P ，Chakkalakal JV ，Boudreault L ，Bélanger G ，Hébert RL ，Renaud JM ，Jasmin BJ ... -  《-》

Analysis of gene expression differences between utrophin/dystrophin-deficient vs mdx skeletal muscles reveals a specific upregulation of slow muscle genes in limb muscles.

Baker PE ，Kearney JA ，Gong B ，Merriam AP ，Kuhn DE ，Porter JD ，Rafael-Fortney JA ... -  《NEUROGENETICS》

Alterations in Notch signalling in skeletal muscles from mdx and dko dystrophic mice and patients with Duchenne muscular dystrophy.

Church JE ，Trieu J ，Chee A ，Naim T ，Gehrig SM ，Lamon S ，Angelini C ，Russell AP ，Lynch GS ... -  《-》