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 3

Genetic alteration of Pdgfrb expression changes muscle regeneration and myotube development.

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Genetic alteration of Pdgfrb expression changes muscle regeneration and ...
(A) Experimental design: ControlPax7, PdgfrbPax7-KO, and PdgfrbPax7-D849V mice received TMX at P60 and subsequently injured with 1.2% BaCl2. TA muscles were analyzed at 7 d.p.i. (B) Representative laminin and eMyHC staining of injured TA sections from the mice described in A. (C) Mean CSA of injured myofibers from images described in B (n = 5 mice/group). (D) Myonuclear number per injured myofiber from the images described in B (n = 5 mice/group). (E) Quantification of eMyHC+ myofibers from the images described in B (n = 5 mice/group). (F) In vitro design: Muscle progenitors isolated from ControlPax7, PdgfrbPax7-KO, and PdgfrbPax7-D849V mice were cultured with TMX, expanded, and differentiated to assess myotube development. (G) Representative Pax7tdTomato and MyHC immunofluorescence images showing myotube formation from cultures in F. (H) Fusion index quantification from cultures in G (n = 3 mice/group). (I) Myotube nuclear number and distribution from cultures in G (n = 4 mice/group). (J) Differentiation index of low-density cultures from ControlPax7, PdgfrbPax7-KO, and PdgfrbPax7-D849V mice, calculated from Pax7tdTomato and myogenin colocalization (n = 5 mice/group). Data represent the mean ± SEM. Statistical significance was determined using 1-way ANOVA (C, E, H, and J) or 2-way ANOVA (D and I) followed by Dunnett’s multiple-comparison test (D and I). Scale bars: 100 μm (B and G). Panels A and F were created using BioRender.