Metabolic remodeling of dystrophic skeletal muscle reveals biological roles for dystrophin and utrophin in adaptation and plasticity.

Preferential damage to fast, glycolytic myofibers is common in many muscle-wasting diseases, including Duchenne muscular dystrophy (DMD). Promoting an oxidative phenotype could protect muscles from damage and ameliorate the dystrophic pathology with therapeutic relevance, but developing efficacious strategies requires understanding currently unknown biological roles for dystrophin and utrophin in dystrophic muscle adaptation and plasticity. Combining whole transcriptome RNA sequencing and mitochondrial proteomics with assessments of metabolic and contractile function, we investigated the roles of dystrophin and utrophin in fast-to-slow muscle remodeling with low-frequency electrical stimulation (LFS, 10 Hz, 12 h/d, 7 d/wk, 28 d) in mdx (dystrophin null) and dko (dystrophin/utrophin null) mice, two established preclinical models of DMD. Novel biological roles in adaptation were demonstrated by impaired transcriptional activation of estrogen-related receptor alpha-responsive genes supporting oxidative phosphorylation in dystrophic muscles. Further, utrophin expression in dystrophic muscles was required for LFS-induced remodeling of mitochondrial respiratory chain complexes, enhanced fiber respiration, and conferred protection from eccentric contraction-mediated damage. These findings reveal novel roles for dystrophin and utrophin during LFS-induced metabolic remodeling of dystrophic muscle and highlight the therapeutic potential of LFS to ameliorate the dystrophic pathology and protect from contraction-induced injury with important implications for DMD and related muscle disorders.

Hardee JP ，Martins KJB ，Miotto PM ，Ryall JG ，Gehrig SM ，Reljic B ，Naim T ，Chung JD ，Trieu J ，Swiderski K ，Philp AM ，Philp A ，Watt MJ ，Stroud DA ，Koopman R ，Steinberg GR ，Lynch GS ... -  《Molecular Metabolism》

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 ... -  《-》

Utrophin influences mitochondrial pathology and oxidative stress in dystrophic muscle.

Kennedy TL ，Moir L ，Hemming S ，Edwards B ，Squire S ，Davies K ，Guiraud S ... -  《Skeletal Muscle》

Increasing muscle contractility through low-frequency stimulation alters tibial bone geometry and reduces bone strength in mdx and dko dystrophic mice.

Chan AS ，Hardee JP ，Blank M ，Cho EH ，McGregor NE ，Sims NA ，Lynch GS ... -  《-》

Embryonic myosin is a regeneration marker to monitor utrophin-based therapies for DMD.

Guiraud S ，Edwards B ，Squire SE ，Moir L ，Berg A ，Babbs A ，Ramadan N ，Wood MJ ，Davies KE ... -  《-》