Duchenne Muscular Dystrophy Fibrosis Potentially Explained by Abnormal NFAT5 Physiology in Duchenne Muscular Dystrophy Fibroblasts | Chapter 8 | New Innovations in Chemistry and Biochemistry Vol. 5

 Chronic inflammation and fibrotic tissue development by fibroblasts characterise Duchenne muscular dystrophy (DMD). Nuclear factor of activated T-cells 5 (NFAT5), a promyogenic factor that responds to hyperosmolar or pro-inflammatory stress, is essentially present in all cells. The lack of NFAT5 causes cell cycle arrest in embryogenic fibroblasts. The goal of this investigation was to see how hyperosmolar or pro-inflammatory stress altered NFAT5 in unaffected and DMD fibroblasts. Unaffected skeletal muscle fibroblasts from one healthy donor demonstrated NFAT5 nuclear translocation and normal cell survival when exposed to hyperosmolar stress. Under pro-inflammatory conditions, the absence of NFAT5 translocation resulted in a reduction in cell proliferation (Incucyte ZOOM). NFAT5 was only found in the nucleus of one DMD patient's skeletal muscle fibroblasts. The physiology of NFAT5 was unaffected by hyperosmolar circumstances or pro-inflammatory cytokines IFN-, IL-1, and TNF- (immunofluorescence, western blotting, RT-qPCR). In undisturbed cell development, hyperosmolarity resulted in lower cell viability and pro-inflammatory stress. These data imply that NFAT5 is required for the survival of DMD fibroblasts. When DMD fibroblasts are exposed to pro-inflammatory or hyperosmolar stress, an unexpected NFAT5 response occurs, in which fibroblasts are not triggered by inflammatory cytokines and cannot resist hyperosmolarity. Chronic inflammation may play a non-restrictive role in the development of fibrosis in DMD. Permanent fibrotic matrix synthesis by DMD cells could be explained molecularly by abnormal NFAT5 physiology.

Author(S) Details

Sandrine Herbelet
Department of Neurology, Ghent University and Ghent University Hospital, C. Heymanslaan 10, 9000 Ghent, Belgium.

Boel De Paepe
Department of Neurology, Ghent University and Ghent University Hospital, C. Heymanslaan 10, 9000 Ghent, Belgium and Neuromuscular Reference Center, Ghent University Hospital, C. Heymanslaan 10, 9000 Ghent, Belgium.

Jan L. De Bleecker
Department of Neurology, Ghent University and Ghent University Hospital, C. Heymanslaan 10, 9000 Ghent, Belgium and Neuromuscular Reference Center, Ghent University Hospital, C. Heymanslaan 10, 9000 Ghent, Belgium.

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