Key result
Inhibition of Postn using shRNA or a neutralizing antibody significantly rescued myogenesis defects in a myotonic dystrophy type 1 myoblast model, increasing myotube area and fusion index.
Why the study?
The underlying mechanism of defective myogenesis in myotonic dystrophy type 1 and the involvement of the extracellular microenvironment remained unknown.
Does Postn inhibition improve myogenesis in a myotonic dystrophy type 1 myoblast model?
Does Postn inhibition improve myogenesis in a myotonic dystrophy type 1 myoblast model?
Inhibition of periostin (Postn) via shRNA or neutralizing antibody rescues myogenesis defects in a DM1 myoblast model, highlighting a potential therapeutic target.
Answers are grounded in this paper and cite their sources.
Postn inhibition may rescue myogenesis in DM1 models; leaves open clinical translation pending in vivo and human studies.
Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disease caused by expanded CTG repeats in the 3′ untranslated region (3′UTR) of the DMPK gene. The myogenesis process is defective in DM1, which is closely associated with progressive muscle weakness and wasting. Despite many proposed explanations for the myogenesis defects in DM1, the underlying mechanism and the involvement of the extracellular microenvironment remained unknown. Here, we constructed a DM1 myoblast cell model and reproduced the myogenesis defects. By RNA sequencing (RNA-seq), we discovered that periostin (Postn) was the most significantly upregulated gene in DM1 myogenesis compared with normal controls. This difference in Postn was confirmed by real-time quantitative PCR (RT-qPCR) and western blotting. Moreover, Postn was found to be significantly upregulated in skeletal muscle and myoblasts of DM1 patients. Next, we knocked down Postn using a short hairpin RNA (shRNA) in DM1 myoblast cells and found that the myogenesis defects in the DM1 group were successfully rescued, as evidenced by increases in the myotube area, the fusion index, and the expression of myogenesis regulatory genes. Similarly, Postn knockdown in normal myoblast cells enhanced myogenesis. As POSTN is a secreted protein, we treated the DM1 myoblast cells with a POSTN-neutralizing antibody and found that DM1 myogenesis defects were successfully rescued by POSTN neutralization. We also tested the myogenic ability of myoblasts in the skeletal muscle injury mouse model and found that Postn knockdown improved the myogenic ability of DM1 myoblasts. The activity of the TGF-β/Smad3 pathway was upregulated during DM1 myogenesis but repressed when inhibiting Postn with a Postn shRNA or a POSTN-neutralizing antibody, which suggested that the TGF-β/Smad3 pathway might mediate the function of Postn in DM1 myogenesis. These results suggest that Postn is a potential therapeutical target for the treatment of myogenesis defects in DM1.
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Shen et al. (2021) studied Myotonic dystrophy type 1 (DM1). Postn knockdown (shRNA) or POSTN-neutralizing antibody vs. Scrambled shRNA or control IgG was evaluated on Myotube area at differentiation day 6 (p=<0.05). Inhibition of Postn using shRNA or a neutralizing antibody significantly rescued myogenesis defects in a myotonic dystrophy type 1 myoblast model, increasing myotube area and fusion index.
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