PT  - JOURNAL ARTICLE
AU  - Maxime R. F. Gosselin
AU  - Virginie Mournetas
AU  - Malgorzata Borczyk
AU  - Lukasz Bozycki
AU  - Michal Korostynski
AU  - Samuel C. Robson
AU  - Christian Pinset
AU  - Dariusz C. Górecki
TI  - Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts
AID  - 10.1101/2021.08.24.457331
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.08.24.457331
4099  - http://biorxiv.org/content/early/2021/11/30/2021.08.24.457331.short
4100  - http://biorxiv.org/content/early/2021/11/30/2021.08.24.457331.full
AB  - Duchenne muscular dystrophy (DMD) affects myofibers and muscle stem cells (SC), causing progressive muscle degeneration and repair defects. It is not known whether dystrophic myoblasts—the effector cells of muscle growth and regeneration—are affected. Using a combination of transcriptomic, molecular and functional analyses we demonstrate, to our knowledge for the first time, convergent cell-autonomous abnormalities in primary mouse and human dystrophic myoblasts. In Dmdmdx mouse myoblasts lacking full-length dystrophin transcripts, expression of 170 other genes was significantly altered. Myod1 (p=2.9e-21) and key muscle genes controlled by MyoD (Myog, Mymk, Mymx, epigenetic regulators, ECM interactors, calcium signalling and fibrosis genes) were significantly downregulated. Gene ontology enrichment analysis indicated significant alterations in genes involved in muscle development and function. These transcriptomic abnormalities translated into increased proliferation (p=3.0e-3), reduced chemotaxis towards both sera-rich (p=3.8e-2) and cytokine-containing medium (p=1.0e-2), and significantly accelerated differentiation in 3D organotypic cultures. These altered myoblast functions are essential for muscle regeneration. The defects were caused by the loss of expression of full-length dystrophin as strikingly similar and not exacerbated alterations were also observed in dystrophin-null Dmdmdx-βgeo myoblasts. Corresponding abnormalities were identified in human DMD primary myoblasts and in an established dystrophic mouse muscle (SC5) cell line, confirming universal, cross-species and cell-autonomous nature of this defect. These results demonstrate the disease continuum: DMD defects in satellite cells cause myoblast dysfunctions diminishing muscle regeneration, which is essential to counteract myofiber degeneration. Contrary to the established belief, our data identify myoblasts as a novel and important therapeutic target for treatment of this lethal disease.Competing Interest StatementThe authors have declared no competing interest.