PDGFRβ signaling restrains myocyte function to limit the regenerative capacity of skeletal muscle
Siwen Xue, Abigail M. Benvie, Jamie E. Blum, Benjamin D. Cosgrove, Anna E. Thalacker-Mercer, Daniel C. Berry
Siwen Xue, Abigail M. Benvie, Jamie E. Blum, Benjamin D. Cosgrove, Anna E. Thalacker-Mercer, Daniel C. Berry
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Research Article Development Muscle biology

PDGFRβ signaling restrains myocyte function to limit the regenerative capacity of skeletal muscle

Abstract

Muscle cell fusion is critical for the formation and maintenance of multinucleated myotubes during skeletal muscle development and regeneration. However, the molecular mechanisms directing cell-cell fusion are not fully understood. Here, we identified platelet-derived growth factor receptor β (PDGFRβ) signaling as a key modulator of myocyte function in adult muscle cells. Our findings demonstrated that genetic deletion of Pdgfrb enhanced muscle regeneration and increased myofiber size, whereas Pdgfrb activation impaired muscle repair. Inhibition of PDGFRβ activity promoted myonuclear accretion in both mouse and human myotubes, whereas PDGFRβ activation stalled myotube development by preventing cell spreading to limit fusion potential. Furthermore, PDGFRβ activity cooperated with TGF-β signaling to regulate myocyte size and fusion. Mechanistically, PDGFRβ signaling required STAT1 activation, and blocking STAT1 phosphorylation enhanced myofiber repair and size during regeneration. Collectively, PDGFRβ signaling acts as a regenerative checkpoint and represents a potential clinical target to improve skeletal muscle repair.

Authors

Siwen Xue, Abigail M. Benvie, Jamie E. Blum, Benjamin D. Cosgrove, Anna E. Thalacker-Mercer, Daniel C. Berry

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Figure 6

STAT1 mediates PDGFRβ signaling to control myocyte fusion and myofiber regeneration.

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STAT1 mediates PDGFRβ signaling to control myocyte fusion and myofiber r...
(A) Experimental design for the in vitro assays. Muscle progenitor cells from ControlMyoG and PdgfrbMyoG-D849V mice were differentiated for 5 days in the presence of vehicle (0.1% DMSO) or fludarabine (1 μM), and myotube formation was assessed. (B) Representative MyoGtdTomato images showing myotube development in the cultures described in A. (C and D) Fusion index (C) and nuclei per myotube (D) from the cultures described in B (n = 3 mice/group). (E) Representative F-actin staining of myocytes isolated from ControlMyoG and PdgfrbMyoG-D849V mice after 1 day of differentiation with vehicle or fludarabine (1 μM). (F) Quantification of cell spreading in the cultures shown in E (n = 4 mice/group). (G) In vivo design: ControlPax7 and PdgfrbPax7-D849V mice received BaCl2 injury (1.2%) followed by daily injections of vehicle or fludarabine (3 mg/kg) for 5 days. TA muscles were analyzed at 7 d.p.i. (H) Representative laminin and eMyHC staining of injured TA sections from the mice described in G. (I) Mean CSA of injured myofibers from the images described in H (n = 5 mice/group). (J) Quantification of eMyHC+ myofibers from the images described in H (n = 5 mice/group). Data represent the mean ± SEM. Statistical significance was determined using 2-way ANOVA (C, D, F, I, and J) followed by Šídák’s or Tukey’s multiple-comparison test. Scale bars: 100 μm. Panels A and G were created using BioRender.