Elsevier

Molecular Metabolism

Volume 45, March 2021, 101157
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2020.101157Get rights and content
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Highlights

  • Transcriptional remodeling to chronic low-frequency electrical stimulation (LFS) is impaired in dystrophic muscles.

  • Loss of dystrophin and utrophin in dystrophic muscles disrupts remodeling of mitochondrial complexes I-III to chronic LFS.

  • Loss of dystrophin and utrophin in dystrophic muscles abrogates improvements in fiber respiration after chronic LFS.

  • Loss of dystrophin and utrophin in dystrophic muscles compromises protection from contraction-induced injury after chronic LFS.

Abstract

Objectives

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.

Methods

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.

Results

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.

Conclusions

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

Muscular dystrophy
Muscle adaptation
Dystrophin
Utrophin
Oxidative metabolism

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