Abstract
Duchenne muscular dystrophy (DMD) is a rare genetic disease due to dystrophin gene mutations which cause progressive weakness and muscle wasting. Circadian rhythm coordinates biological processes with the 24-h cycle and it plays a key role in maintaining muscle functions, both in animal models and in humans. We explored expression profiles of circadian circuit master genes both in Duchenne muscular dystrophy skeletal muscle and in its animal model, the mdx mouse. We designed a customized, mouse-specific Fluidic-Card-TaqMan-based assay (Fluid-CIRC) containing thirty-two genes related to circadian rhythm and muscle regeneration and analyzed gastrocnemius and tibialis anterior muscles from both unexercised and exercised mdx mice. Based on this first analysis, we prioritized the 7 most deregulated genes in mdx mice and tested their expression in skeletal muscle biopsies from 10 Duchenne patients. We found that CSNK1E, SIRT1, and MYOG are upregulated in DMD patient biopsies, consistent with the mdx data. We also demonstrated that their proteins are detectable and measurable in the DMD patients’ plasma. We suggest that CSNK1E, SIRT1, and MYOG might represent exploratory circadian biomarkers in DMD.
Highlights
The dystrophin gene (DMD) (OMIM 300377), located in Xp21.2-p21.1, is a 2,2 Mb gene that encodes for the dystrophin protein (DYS), a subsarcolemmal, rod-shaped protein of 427kDa involved in the formation of the dystrophin-associated protein complex (DAPC) (Ervasti and Campbell, 1993)
In order to explore the involvement of circadian genes in dystrophinopathies, we designed a custom TaqMan Low Density Array (TLDA) micro fluidic-card, Fluid-CIRC, to obtain the transcriptional profiling of two different mdx muscles: gastrocnemius (GC) and tibialis anterior (TA) derived from both sedentary and trained mice
Exploratory biomarkers were extensively searched in the mdx mice and in Duchenne muscular dystrophy (DMD) patients since having available robust biomarkers would greatly benefit the optimization of patient treatments
Summary
The dystrophin gene (DMD) (OMIM 300377), located in Xp21.2-p21.1, is a 2,2 Mb gene that encodes for the dystrophin protein (DYS), a subsarcolemmal, rod-shaped protein of 427kDa involved in the formation of the dystrophin-associated protein complex (DAPC) (Ervasti and Campbell, 1993). The DAPC is composed of dystroglycans, sarcoglycans, sarcospan, dystrobrevins, Circadian Gene as DMD’s Exploratory Biomarkers and syntrophin. This complex exerts the structural function of mechanic-transducer between muscle fibers and the extracellular matrix and controls membrane stability. A large variety of dystrophin gene mutations (approximately 75% of deletions/duplications and 25% of small/atypical mutations) cause dystrophinopathies (see in DMD Leiden pages). Mutations maintaining the reading frame are generally associated with Becker muscular dystrophy (BMD) and other milder or atypical allelic forms of dystrophinopathies (OMIM 300376). Frameshifting mutations are mainly associated with severe Duchenne muscular dystrophy (DMD OMIM 310200) and cause a complete absence or severe reduction of the dystrophin protein. Dystrophin-deficient fibers are more prone to membrane damage following muscle contraction. After a number of degenerative-regenerative cycles, regeneration fails and there is the complete fibrotic substitution of muscle tissue (Massopust et al, 2020)
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