Journal
HUMAN MOLECULAR GENETICS
Volume 28, Issue 8, Pages 1244-1259Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddy405
Keywords
-
Funding
- CoMPLEX-UCL PhD studentship
- British Heart Foundation [SP/08/004, PG/13/1930059]
- Foulkes Foundation Fellowship
- FSH Society [FSHS-82016-03]
- Muscular Dystrophy UK [RA3/3052/1]
- FSH Society Postdoctoral Fellowship [FSHS-82017-05]
- Wellcome Trust PhD Studentship [WT -203949/Z/16/Z]
- King's Health Partners R&D Challenge Fund [R151006]
- Medical Research Council [MR/P023215/1]
- Royal Society
- EPSRC
- National Natural Science Foundation of China
- FSH Society Shack Family and Friends research grant [FSHS-82013-06]
- Association Francaise contre les Myopathies [17865]
- BIODESIGN from EU FP7 [262948]
- Wellcome Trust [203949/Z/16/Z] Funding Source: Wellcome Trust
- Muscular Dystrophy UK [RA3/3052] Funding Source: researchfish
- MRC [MR/S002472/1, MR/P023215/1] Funding Source: UKRI
Ask authors/readers for more resources
Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy, linked to epigenetic derepression of D4Z4 repeats on chromosome 4q, leading to ectopic DUX4 expression. FSHD patient myoblasts have defective myogenic differentiation, forming smaller myotubes with reduced myosin content. However, molecular mechanisms driving such disrupted myogenesis in FSHD are poorly understood. We performed high-throughput morphological analysis describing FSHD and control myogenesis, revealing altered myogenic differentiation results in hypotrophic myotubes. Employing polynomial models and an empirical Bayes approach, we established eight critical time points during which human healthy and FSHD myogenesis differ. RNA-sequencing at these eight nodal time points in triplicate, provided temporal depth for a multivariate regression analysis, allowing assessment of interaction between progression of differentiation and FSHD disease status. Importantly, the unique size and structure of our data permitted identification of many novel FSHD pathomechanisms undetectable by previous approaches. For further analysis here, we selected pathways that control mitochondria: of interest considering known alterations in mitochondrial structure and function in FSHD muscle, and sensitivity of FSHD cells to oxidative stress. Notably, we identified suppression of mitochondrial biogenesis, in particular via peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1 alpha), the cofactor and activator of oestrogen-related receptor alpha (ERR alpha). PGC1 alpha knock-down caused hypotrophic myotubes to form from control myoblasts. Known ERRa agonists and safe food supplements biochanin A, daidzein or genistein, each rescued the hypotrophic FSHD myotube phenotype. Together our work describes transcriptomic changes in high resolution that occur during myogenesis in FSHD ex vivo, identifying suppression of the PGC1a-ERRa axis leading to perturbed myogenic differentiation, which can effectively be rescued by readily available food supplements.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available