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

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. Although no natural animal models of FSHD exist,...

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Bibliographic Details
Published in:Disease models & mechanisms 2021-08, Vol.14 (8)
Main Authors: Nunes, Andreia M, Ramirez, Monique, Jones, Takako I, Jones, Peter L
Format: Article
Language:English
Subjects:
Animals
biomarker
Biomarkers
Biomarkers - metabolism
Biopsy
Clinical trials
Disease
dux4
Epigenetics
fshd
Gene expression
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Kinases
Magnetic resonance imaging
Mice
MicroRNAs
MicroRNAs - genetics
MicroRNAs - metabolism
mir-206
mirna
Muscle, Skeletal - pathology
Muscular dystrophy
Muscular Dystrophy, Facioscapulohumeral - pathology
Musculoskeletal system
Mutation
Neuromuscular Disease Models
Pathophysiology
Patients
Proteins
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Summary: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. Although 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 established 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. This article has an associated First Person interview with the first author of the paper.
ISSN:1754-8403
1754-8411
1754-8411
DOI:10.1242/dmm.049016