scholarly journals A revised model for mitochondrial dysfunction in Duchenne muscular dystrophy

2021 ◽  
Vol 31 (3) ◽  
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.

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

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

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

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.

scholarly journals The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 648
Author(s):  
Andrea L. Reid ◽  
Matthew S. Alexander
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mitochondrial Dysfunction ◽  
Disease Onset ◽  
Exon Skipping ◽  
Dystrophin Gene ◽  
Muscle Disease ◽  
Mitochondrial Morphology ◽  
Gene Therapies ◽  
Dystrophin Protein

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.

scholarly journals Degenerative and regenerative pathways underlying Duchenne muscular dystrophy revealed by single-nucleus RNA sequencing

2020 ◽  
Vol 117 (47) ◽  
pp. 29691-29701 ◽  
Author(s):  
Francesco Chemello ◽  
Zhaoning Wang ◽  
Hui Li ◽  
John R. McAnally ◽  
Ning Liu ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Dystrophin Gene ◽  
Cell Types ◽  
Muscle Pathology ◽  
Dystrophic Muscle ◽  
Nonmuscle Cell ◽  
Prevalent Disease ◽  
Single Nucleus ◽  
Muscle Disorder

Duchenne muscular dystrophy (DMD) is a fatal muscle disorder characterized by cycles of degeneration and regeneration of multinucleated myofibers and pathological activation of a variety of other muscle-associated cell types. The extent to which different nuclei within the shared cytoplasm of a myofiber may display transcriptional diversity and whether individual nuclei within a multinucleated myofiber might respond differentially to DMD pathogenesis is unknown. Similarly, the potential transcriptional diversity among nonmuscle cell types within dystrophic muscle has not been explored. Here, we describe the creation of a mouse model of DMD caused by deletion of exon 51 of the dystrophin gene, which represents a prevalent disease-causing mutation in humans. To understand the transcriptional abnormalities and heterogeneity associated with myofiber nuclei, as well as other mononucleated cell types that contribute to the muscle pathology associated with DMD, we performed single-nucleus transcriptomics of skeletal muscle of mice with dystrophin exon 51 deletion. Our results reveal distinctive and previously unrecognized myonuclear subtypes within dystrophic myofibers and uncover degenerative and regenerative transcriptional pathways underlying DMD pathogenesis. Our findings provide insights into the molecular underpinnings of DMD, controlled by the transcriptional activity of different types of muscle and nonmuscle nuclei.

scholarly journals Mutation-independent Proteomic Signatures of Pathological Progression in Murine Models of Duchenne Muscular Dystrophy

2020 ◽  
Vol 19 (12) ◽  
pp. 2047-2067
Author(s):  
Tirsa L. E. van Westering ◽  
Henrik J. Johansson ◽  
Britt Hanson ◽  
Anna M. L. Coenen-Stass ◽  
Yulia Lomonosova ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Growth ◽  
Differentially Expressed ◽  
Murine Models ◽  
Dystrophic Muscle ◽  
C2c12 Myoblasts ◽  
Experimental Therapies ◽  
Dystrophin Protein ◽  
Upstream Regulators

The absence of the dystrophin protein in Duchenne muscular dystrophy (DMD) results in myofiber fragility and a plethora of downstream secondary pathologies. Although a variety of experimental therapies are in development, achieving effective treatments for DMD remains exceptionally challenging, not least because the pathological consequences of dystrophin loss are incompletely understood. Here we have performed proteome profiling in tibialis anterior muscles from two murine DMD models (mdx and mdx52) at three ages (8, 16, and 80 weeks of age), all n = 3. High-resolution isoelectric focusing liquid chromatography-tandem MS (HiRIEF-LC–MS/MS) was used to quantify the expression of 4974 proteins across all 27 samples. The two dystrophic models were found to be highly similar, whereas multiple proteins were differentially expressed relative to WT (C57BL/6) controls at each age. Furthermore, 1795 proteins were differentially expressed when samples were pooled across ages and dystrophic strains. These included numerous proteins associated with the extracellular matrix and muscle function that have not been reported previously. Pathway analysis revealed multiple perturbed pathways and predicted upstream regulators, which together are indicative of cross-talk between inflammatory, metabolic, and muscle growth pathways (e.g. TNF, INFγ, NF-κB, SIRT1, AMPK, PGC-1α, PPARs, ILK, and AKT/PI3K). Upregulation of CAV3, MVP and PAK1 protein expression was validated in dystrophic muscle by Western blot. Furthermore, MVP was upregulated during, but not required for, the differentiation of C2C12 myoblasts suggesting that this protein may affect muscle regeneration. This study provides novel insights into mutation-independent proteomic signatures characteristic of the dystrophic phenotype and its progression with aging.

scholarly journals Function and Genetics of Dystrophin and Dystrophin-Related Proteins in Muscle

2002 ◽  
Vol 82 (2) ◽  
pp. 291-329 ◽  
Author(s):  
Derek J. Blake ◽  
Andrew Weir ◽  
Sarah E. Newey ◽  
Kay E. Davies
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Protein Complex ◽  
Muscle Disease ◽  
Calcium Handling ◽  
Dystrophic Muscle ◽  
Gene Encoding ◽  
Muscle Wasting Disease ◽  
Novel Therapeutic Strategies ◽  
Related Proteins

The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. There is currently no effective treatment for the disease; however, the complex molecular pathology of this disorder is now being unravelled. Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function. Although the precise function of dystrophin is unknown, the lack of protein causes membrane destabilization and the activation of multiple pathophysiological processes, many of which converge on alterations in intracellular calcium handling. Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle. This family includes utrophin and α-dystrobrevin, which are involved in the maintenance of the neuromuscular junction architecture and in muscle homeostasis. New insights into the pathophysiology of dystrophic muscle, the identification of compensating proteins, and the discovery of new binding partners are paving the way for novel therapeutic strategies to treat this fatal muscle disease. This review discusses the role of the dystrophin complex and protein family in muscle and describes the physiological processes that are affected in Duchenne muscular dystrophy.

Glucocorticoid Treatment for the Prevention of Scoliosis in Children with Duchenne Muscular Dystrophy: Long-Term Follow-up

2013 ◽  
Vol 95 (12) ◽  
pp. 1057-1061 ◽  
Author(s):  
David E Lebel ◽  
John A Corston ◽  
Laura C McAdam ◽  
W Douglas Biggar ◽  
Benjamin A Alman
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Glucocorticoid Treatment ◽  
Long Term Follow Up

scholarly journals Emerging strategies for cell and gene therapy of the muscular dystrophies

2009 ◽  
Vol 11 ◽  
Author(s):  
Lindsey A. Muir ◽  
Jeffrey S. Chamberlain
Keyword(s):  
Gene Therapy ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Myotonic Dystrophy ◽  
Trinucleotide Repeat ◽  
Chromosome 1 ◽  
Muscular Dystrophies ◽  
Dystrophic Muscle ◽  
Kinase Gene ◽  
Wide Range

The muscular dystrophies are a heterogeneous group of over 40 disorders that are characterised by muscle weakness and wasting. The most common are Duchenne muscular dystrophy and Becker muscular dystrophy, which result from mutations within the gene encoding dystrophin; myotonic dystrophy type 1, which results from an expanded trinucleotide repeat in the myotonic dystrophy protein kinase gene; and facioscapulohumeral dystrophy, which is associated with contractions in the subtelomeric region of human chromosome 1. Currently the only treatments involve clinical management of symptoms, although several promising experimental strategies are emerging. These include gene therapy using adeno-associated viral, lentiviral and adenoviral vectors and nonviral vectors, such as plasmid DNA. Exon-skipping and cell-based therapies have also shown promise in the effective treatment and regeneration of dystrophic muscle. The availability of numerous animal models for Duchenne muscular dystrophy has enabled extensive testing of a wide range of therapeutic approaches for this type of disorder. Consequently, we focus here on the therapeutic developments for Duchenne muscular dystrophy as a model of the types of approaches being considered for various types of dystrophy. We discuss the advantages and limitations of each therapeutic strategy, as well as prospects and recent successes in the context of future clinical applications.

Long-Term Outcome of Interdisciplinary Management of Patients with Duchenne Muscular Dystrophy Receiving Daily Glucocorticoid Treatment

2017 ◽  
Vol 182 ◽  
pp. 296-303.e1 ◽  
Author(s):  
Brenda L. Wong ◽  
Irina Rybalsky ◽  
Karen C. Shellenbarger ◽  
Cuixia Tian ◽  
Mary A. McMahon ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Interdisciplinary Management ◽  
Glucocorticoid Treatment ◽  
Term Outcome ◽  
Long Term Outcome

scholarly journals Adipose Tissue-Derived Stem Cell Secreted IGF-1 Protects Myoblasts from the Negative Effect of Myostatin

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Sebastian Gehmert ◽  
Carina Wenzel ◽  
Markus Loibl ◽  
Gero Brockhoff ◽  
Michaela Huber ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Stem Cell ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Protective Effect ◽  
Conditioned Medium ◽  
Therapeutic Option ◽  
Dystrophic Muscle ◽  
Rnai Technology ◽  
Myod Expression

Myostatin, a TGF-βfamily member, is associated with inhibition of muscle growth and differentiation and might interact with the IGF-1 signaling pathway. Since IGF-1 is secreted at a bioactive level by adipose tissue-derived mesenchymal stem cells (ASCs), these cells (ASCs) provide a therapeutic option for Duchenne Muscular Dystrophy (DMD). But the protective effect of stem cell secreted IGF-1 on myoblast under high level of myostatin remains unclear. In the present study murine myoblasts were exposed to myostatin under presence of ASCs conditioned medium and investigated for proliferation and apoptosis. The protective effect of IGF-1 was further examined by using IGF-1 neutralizing and receptor antibodies as well as gene silencing RNAi technology. MyoD expression was detected to identify impact of IGF-1 on myoblasts differentiation when exposed to myostatin. IGF-1 was accountable for 43.6% of the antiapoptotic impact and 48.8% for the proliferative effect of ASCs conditioned medium. Furthermore, IGF-1 restored mRNA and protein MyoD expression of myoblasts under risk. Beside fusion and transdifferentiation the beneficial effect of ASCs is mediated by paracrine secreted cytokines, particularly IGF-1. The present study underlines the potential of ASCs as a therapeutic option for Duchenne muscular dystrophy and other dystrophic muscle diseases.

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