Hardee 2020 Mol Metab

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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 (2020) Metabolic remodeling of dystrophic skeletal muscle reveals biological roles for dystrophin and utrophin in adaptation and plasticity. Mol Metab [Epub ahead of print].

» PMID: 33359740 Open Access

Hardee Justin P, Martins Karen J B, Miotto Paula M, Ryall James G, Gehrig Stefan M, Reljic Boris, Naim Timur, Chung Jin D, Trieu Jen, Swiderski Kristy, Philp Ashleigh M, Philp Andrew, Watt Matthew J, Stroud David A, Koopman Rene, Steinberg Gregory R, Lynch Gordon S (2020) Mol Metab

Abstract: 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.

Keywords: Dystrophin, Muscle adaptation, Muscular dystrophy, Oxidative metabolism, Utrophin Bioblast editor: Plangger M O2k-Network Lab: AU Melbourne Hardee JP, AU Sydney Philp A


Labels: MiParea: Respiration, Genetic knockout;overexpression 


Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 


Coupling state: LEAK, OXPHOS  Pathway: N, NS  HRR: Oxygraph-2k 

2021-02