Melanocytes—A novel tool to study mitochondrial dysfunction in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a pathogenic disruption of the DYSTROPHIN gene that results in non-functional dystrophin protein. DMD patients experience loss of ambulation, cardiac arrhythmia, metabolic syndrome, and respiratory failure. At the molecular level, the lack of dystrophin in the muscle results in myofiber death, fibrotic infiltration, and mitochondrial dysfunction. There is no cure for DMD, although dystrophin-replacement gene therapies and exon-skipping approaches are being pursued in clinical trials. Mitochondrial dysfunction is one of the first cellular changes seen in DMD myofibers, occurring prior to muscle disease onset and progresses with disease severity. This is seen by reduced mitochondrial function, abnormal mitochondrial morphology and impaired mitophagy (degradation of damaged mitochondria). Dysfunctional mitochondria release high levels of reactive oxygen species (ROS), which can activate pro-inflammatory pathways such as IL-1β and IL-6. Impaired mitophagy in DMD results in increased inflammation and further aggravates disease pathology, evidenced by increased muscle damage and increased fibrosis. This review will focus on the critical interplay between mitophagy and inflammation in Duchenne muscular dystrophy as a pathological mechanism, as well as describe both candidate and established therapeutic targets that regulate these pathways.

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Mitochondrial Dysfunction in Duchenne Muscular Dystrophy

Open Journal of Endocrine and Metabolic Diseases ◽

10.4236/ojemd.2014.48020 ◽

2014 ◽

Vol 04 (08) ◽

pp. 211-218 ◽

Cited By ~ 7

Author(s):

Marie Kelly-Worden ◽

Emily Thomas

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mitochondrial Dysfunction

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O.3MiR-379 link glucocorticoid treatment to mitochondrial dysfunction in Duchenne muscular dystrophy

Neuromuscular Disorders ◽

10.1016/j.nmd.2019.06.022 ◽

2019 ◽

Vol 29 ◽

pp. S38-S39

Author(s):

M. Sanson ◽

E. Massourides ◽

V. Mournetas ◽

A. Vu Hong ◽

P. Bénit ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mitochondrial Dysfunction ◽

Glucocorticoid Treatment

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Abstract 44: Telomere and Mitochondrial Dysfunction in Duchenne Muscular Dystrophy

Circulation Research ◽

10.1161/res.117.suppl_1.44 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Alex C Chang ◽

Sang-Ging Ong ◽

Joseph Wu ◽

Helen M Blau

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Dilated Cardiomyopathy ◽

Mitochondrial Dysfunction ◽

Telomere Length ◽

Dystrophin Gene ◽

Glycoprotein Complex ◽

The Difference

Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive disease that is result of mutations in the dystrophin gene and is the most common myopathic disease in humans with a prevalence of one in every 3500 males. Dystrophin is crucial for the formation of a dystrophin-glycoprotein complex (DGC), which connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix in both skeletal and cardiac muscles. In the heart, loss of dystrophin leads to increased fibrosis and death in the third decade of life due to dilated cardiomyopathy. A conundrum in studying and developing therapies for DMD has been the lack of a mouse model that fully recapitulates the clinical phenotype, as mice that lack dystrophin (mdx model), unlike patients, exhibit only mild skeletal muscle defects, essentially no cardiac defects and have a relatively normal lifespan. Our lab reasoned that the difference in the manifestation of the disease in mice and humans could be telomere length, as mice have substantially longer telomeres than humans. We created a novel mouse model with shortened telomere lengths (similar to humans) that fully recapitulates the skeletal muscle (Cell. 2010;143:1059-1071; the mdx/mTRKO model) and cardiac muscle phenotype of DMD (Nat Cell Biol. 2013; 15:895-904; dilated cardiomyopathy). Interestingly, we observed a relative 45% reduction in cardiomyocyte telomere length in our mdx/mTRKO animals (3 animals per group, N = 300-400) as well as patient samples (4 DMD patient samples, N = 40-95). Here we present new evidence of mitochondrial dysfunction and telomere dysfunction.

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Melanocytes — A novel tool to study mitochondrial dysfunction in Duchenne muscular dystrophy

Biochimica et Biophysica Acta (BBA) - Bioenergetics ◽

10.1016/j.bbabio.2012.06.417 ◽

2012 ◽

Vol 1817 ◽

pp. S159

Author(s):

C. Pellegrini ◽

A. Zulian ◽

F. Gualandi ◽

E. Manzati ◽

L. Merlini ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mitochondrial Dysfunction

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A revised model for mitochondrial dysfunction in Duchenne muscular dystrophy

European Journal of Translational Myology ◽

10.4081/ejtm.2021.10012 ◽

2021 ◽

Vol 31 (3) ◽

Cited By ~ 1

Author(s):

Ai Vu Hong ◽

Mathilde Sanson ◽

Isabelle Richard ◽

David Israeli

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mitochondrial Dysfunction ◽

Atp Synthesis ◽

Signaling Cascade ◽

Synthesis Rate ◽

Mitochondrial Oxidative Phosphorylation ◽

Dystrophic Muscle ◽

Glucocorticoid Treatment ◽

Mitochondrial Atp Synthase

We recently identified a signaling pathway that links the upregulation of miR-379 with a mitochondrial response in dystrophic muscle. In the present commentary, we explain the significance that this pathway may have in mitochondrial dysfunction in Duchenne muscular dystrophy (DMD). We identified the upregulation of miR-379 in the serum and muscles of DMD animal models and patients. We found that miR-379 is one of very few miRNAs whose expression was normalized in DMD patients treated with glucocorticoid. We identified EIF4G2 as a miR-379 target, which may promote mitochondrial oxidative phosphorylation (OxPhos) in the skeletal muscle. We found enriched EIF4G2 expression in oxidative fibers, and identified the mitochondrial ATP synthase subunit DAPIT as a translational target of EIF4G2. The identified signaling cascade, which comprises miR-379, EIF4G2 and DAPIT, may link the glucocorticoid treatment in DMD to a recovered mitochondrial ATP synthesis rate. We propose an updated model of mitochondrial dysfunction in DMD.

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Dlk1-Dio3 cluster miRNAs regulate mitochondrial functions in Duchenne muscular dystrophy

10.1101/2021.10.20.464950 ◽

2021 ◽

Author(s):

Ai VU Hong ◽

Nathalie Bourg ◽

Peggy Sanatine ◽

Jerome Poupiot ◽

Karine Charton ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mitochondrial Dysfunction ◽

Muscular Dystrophies ◽

Mirna Cluster ◽

Biological Functions ◽

Dystrophic Muscle ◽

Mitochondrial Functions ◽

Mirnas Expression

Background: Duchenne Muscular Dystrophy (DMD) is a severe muscle disease caused by impaired expression of dystrophin. While mitochondrial dysfunction is thought to play an important role in DMD, the mechanism of this dysfunction remains to be clarified. We recently identified in DMD and in other muscular dystrophies the upregulation of a large number of the Dlk1-Dio3 clustered miRNAs (DD-miRNAs), in both the muscle and the serum. The objective of the present study was to define the biological functions of DD-miRNAs in skeletal muscle, particularly in the context of muscular dystrophy. Methods: DD-miRNAs expression pattern was characterized in vitro and in vivo, in normal and dystrophic situations. Epigenomic characterization was performed, to elucidate the molecular control of DD-miRNAs dysregulation. The biological effect of muscle DD-miRNAs dysregulation was investigated by an in vivo simultaneous overexpression of 14 DD-miRNAs in the wild-type muscle, together with CRISPR-Cas9-based knockdown of the entire DD-miRNA cluster in an iPS-derived myotubes. Omics data and bioinformatics tools were used for the prediction of DD-miRNAs biological functions, and functional characterization of mitochondrial pathways was performed. Results: We found that DD-miRNAs dysregulation is not specific to DMD since observed in mouse models for other muscular dystrophies. We showed that DD-miRNAs expression in mdx, is reduced in satellite cells, but highly upregulated in regenerating myofibers, suggesting a myofibers origin of DD6miRNA upregulation in muscular dystrophy in both muscles and serum. We demonstrated that upregulation of DD-miRNAs in the dystrophic muscle is controlled epigenetically by DNA and histone methylation (p<0.0001 and p=0.001, respectively) at the Intergenic Differentially Methylated Region (IG-DMR) of Dlk1-Dio3 locus. Transcriptomic analysis revealed a substantial overlap between the dystrophic muscle of the mdx mouse and the normal muscle that overexpressed 14 DD-miRNAs. Bioinformatics analysis predicted that DD-miRNAs could regulate mitochondrial functions. The ectopic overexpression of 14 DD-miRNAs, in the healthy muscle, resulted in a drastic downregulation of mitochondrial oxidative phosphorylation (OxPhos) (NES=-2.8, p=8.7E-17), similarly to the level in dystrophic muscles of mdx mice and DMD patients (NES=-2.88, p=7.7E-28). Knocking down the entire DD-miRNA cluster in iPS-derived myotubes resulted in increased mitochondrial OxPhos expression and activities. Conclusions: The present study provides evidence for the modulation of mitochondrial activity in the dystrophic muscle by the upregulated DD-miRNAs and supports an updated model for mitochondrial dysfunction in DMD. The regulation of mitochondrial OxPhos by DD-miRNAs may have a broader impact beyond DMD in physiological and pathological situations of muscle adaptation and regeneration.

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