scholarly journals Identification of candidate miRNA biomarkers for facioscapulohumeral muscular dystrophy using DUX4-based mouse models

2021 ◽  
Author(s):  
Andreia M. Nunes ◽  
Monique Ramirez ◽  
Takako I. Jones ◽  
Peter L. Jones
Keyword(s):  
Muscular Dystrophy ◽  
Mouse Model ◽  
Mouse Models ◽  
Skeletal Muscles ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Muscle Pathology ◽  
Aged Mouse ◽  
Serum Samples ◽  
Key Aspects ◽  
Different Levels

Facioscapulohumeral muscular dystrophy (FSHD) is caused by misexpression of DUX4 in skeletal myocytes. As DUX4 is the key therapeutic target in FSHD, surrogate biomarkers of DUX4 expression in skeletal muscle are critically needed for clinical trials. While no natural animal models of FSHD exist, transgenic mice with inducible DUX4 expression in skeletal muscles rapidly develop myopathic phenotypes consistent with FSHD. Here, we establish a new, more accurate FSHD-like mouse model based on chronic DUX4 expression in a small fraction of skeletal myonuclei that develops pathology mimicking key aspects of FSHD across its lifespan. Utilizing this new aged mouse model and DUX4-inducible mouse models, we characterized the DUX4-related microRNA signatures in skeletal muscles, which represent potential biomarkers for FSHD. We found increased expression of miR-31-5p and miR-206 in muscles expressing different levels of DUX4 and displaying varying degrees of pathology. Importantly, miR-206 expression is significantly increased in serum samples from FSHD patients compared with healthy controls. Our data support miR-31-5p and miR-206 as new potential regulators of muscle pathology and miR-206 as a potential circulating biomarker for FSHD.

scholarly journals Enhanced Ca2+ influx from STIM1–Orai1 induces muscle pathology in mouse models of muscular dystrophy

2014 ◽  
Vol 23 (14) ◽  
pp. 3706-3715 ◽  
Author(s):  
Sanjeewa A. Goonasekera ◽  
Jennifer Davis ◽  
Jennifer Q. Kwong ◽  
Federica Accornero ◽  
Lan Wei-LaPierre ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Mouse Models ◽  
Muscle Pathology

scholarly journals Human miRNA miR-675 inhibits DUX4 expression and may be exploited as a potential treatment for Facioscapulohumeral muscular dystrophy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nizar Y. Saad ◽  
Mustafa Al-Kharsan ◽  
Sara E. Garwick-Coppens ◽  
Gholamhossein Amini Chermahini ◽  
Madison A. Harper ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Muscular Dystrophy ◽  
Small Molecules ◽  
Skeletal Muscles ◽  
Disease Gene ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Potential Treatment ◽  
Cell Models ◽  
Powerful Approach ◽  
Dominant Disease

AbstractFacioscapulohumeral muscular dystrophy (FSHD) is a potentially devastating myopathy caused by de-repression of the DUX4 gene in skeletal muscles. Effective therapies will likely involve DUX4 inhibition. RNA interference (RNAi) is one powerful approach to inhibit DUX4, and we previously described a RNAi gene therapy to achieve DUX4 silencing in FSHD cells and mice using engineered microRNAs. Here we report a strategy to direct RNAi against DUX4 using the natural microRNA miR-675, which is derived from the lncRNA H19. Human miR-675 inhibits DUX4 expression and associated outcomes in FSHD cell models. In addition, miR-675 delivery using gene therapy protects muscles from DUX4-associated death in mice. Finally, we show that three known miR-675-upregulating small molecules inhibit DUX4 and DUX4-activated FSHD biomarkers in FSHD patient-derived myotubes. To our knowledge, this is the first study demonstrating the use of small molecules to suppress a dominant disease gene using an RNAi mechanism.

scholarly journals A modified diet does not ameliorate muscle pathology in a mouse model for Duchenne muscular dystrophy

PLoS ONE ◽  
2019 ◽  
Vol 14 (4) ◽  
pp. e0215335
Author(s):  
Ingrid E. C. Verhaart ◽  
Davy van de Vijver ◽  
Joke W. Boertje-van der Meulen ◽  
Kayleigh Putker ◽  
Kevin Adamzek ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Muscle Pathology ◽  
Modified Diet

scholarly journals Overexpression of Galgt2 in skeletal muscle prevents injury resulting from eccentric contractions in both mdx and wild-type mice

2009 ◽  
Vol 296 (3) ◽  
pp. C476-C488 ◽  
Author(s):  
Paul T. Martin ◽  
Rui Xu ◽  
Louise R. Rodino-Klapac ◽  
Elaine Oglesbay ◽  
Marybeth Camboni ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Transgenic Mice ◽  
Skeletal Muscles ◽  
Eccentric Contractions ◽  
Cytotoxic T Cell ◽  
Muscle Pathology ◽  
Mdx Mice ◽  
Specific Force ◽  
Wild Type

The cytotoxic T cell (CT) GalNAc transferase, or Galgt2, is a UDP-GalNAc:β1,4- N-acetylgalactosaminyltransferase that is localized to the neuromuscular synapse in adult skeletal muscle, where it creates the synaptic CT carbohydrate antigen {GalNAcβ1,4[NeuAc(orGc)α2, 3]Galβ1,4GlcNAcβ-}. Overexpression of Galgt2 in the skeletal muscles of transgenic mice inhibits the development of muscular dystrophy in mdx mice, a model for Duchenne muscular dystrophy. Here, we provide physiological evidence as to how Galgt2 may inhibit the development of muscle pathology in mdx animals. Both Galgt2 transgenic wild-type and mdx skeletal muscles showed a marked improvement in normalized isometric force during repetitive eccentric contractions relative to nontransgenic littermates, even using a paradigm where nontransgenic muscles had force reductions of 95% or more. Muscles from Galgt2 transgenic mice, however, showed a significant decrement in normalized specific force and in hindlimb and forelimb grip strength at some ages. Overexpression of Galgt2 in muscles of young adult mdx mice, where Galgt2 has no effect on muscle size, also caused a significant decrease in force drop during eccentric contractions and increased normalized specific force. A comparison of Galgt2 and microdystrophin overexpression using a therapeutically relevant intravascular gene delivery protocol showed Galgt2 was as effective as microdystrophin at preventing loss of force during eccentric contractions. These experiments provide a mechanism to explain why Galgt2 overexpression inhibits muscular dystrophy in mdx muscles. That overexpression also prevents loss of force in nondystrophic muscles suggests that Galgt2 is a therapeutic target with broad potential applications.

scholarly journals Identification of the hyaluronic acid pathway as a therapeutic target for facioscapulohumeral muscular dystrophy

2019 ◽  
Vol 5 (12) ◽  
pp. eaaw7099 ◽  
Author(s):  
Alec M. DeSimone ◽  
John Leszyk ◽  
Kathryn Wagner ◽  
Charles P. Emerson
Keyword(s):  
Hyaluronic Acid ◽  
Muscular Dystrophy ◽  
Transcriptional Activity ◽  
Cell Model ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Muscle Pathology ◽  
Limited Effect ◽  
Central Function ◽  
Rna Granules ◽  
Acid Pathway

Facioscapulohumeral muscular dystrophy (FSHD) is linked to epigenetic derepression of the germline/embryonic transcription factor DUX4 in skeletal muscle. However, the etiology of muscle pathology is not fully understood, as DUX4 misexpression is not tightly correlated with disease severity. Using a DUX4-inducible cell model, we show that multiple DUX4-induced molecular pathologies that have been observed in patient-derived disease models are mediated by the signaling molecule hyaluronic acid (HA), which accumulates following DUX4 induction. These pathologies include formation of RNA granules, FUS aggregation, DNA damage, caspase activation, and cell death. We also observe previously unidentified pathologies including mislocalization of mitochondria and the DUX4- and HA-binding protein C1QBP. These pathologies are prevented by 4-methylumbelliferone, an inhibitor of HA biosynthesis. Critically, 4-methylumbelliferone does not disrupt DUX4-C1QBP binding and has only a limited effect on DUX4 transcriptional activity, establishing that HA signaling has a central function in pathology and is a target for FSHD therapeutics.

scholarly journals Increased plasma lipid levels exacerbate muscle pathology in the mdx mouse model of Duchenne muscular dystrophy

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Nadia Milad ◽  
Zoe White ◽  
Arash Y. Tehrani ◽  
Stephanie Sellers ◽  
Fabio M.V. Rossi ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Plasma Lipid ◽  
Muscle Pathology ◽  
Mdx Mouse ◽  
Lipid Levels

Increased sarcolipin expression and decreased sarco(endo)plasmic reticulum Ca2+ uptake in skeletal muscles of mouse models of Duchenne muscular dystrophy

2013 ◽  
Vol 34 (5-6) ◽  
pp. 349-356 ◽  
Author(s):  
Joel S. Schneider ◽  
Mayilvahanan Shanmugam ◽  
James Patrick Gonzalez ◽  
Henderson Lopez ◽  
Richard Gordan ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Models ◽  
Skeletal Muscles ◽  
Plasmic Reticulum

scholarly journals Effects of CaMKII activity on cardiac and skeletal muscle pathology in a mouse model of Duchenne muscular dystrophy (1102.3)

2014 ◽  
Vol 28 (S1) ◽  
Author(s):  
Nicolette Johnson ◽  
Jennifer Levy ◽  
Isabella Grumbach ◽  
Mark Anderson ◽  
Kevin Campbell
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Muscle Pathology
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