TGF-β–driven muscle degeneration and failed regeneration underlie disease onset in a DMD mouse model
Davi A.G. Mázala, James S. Novak, Marshall W. Hogarth, Marie Nearing, Prabhat Adusumalli, Christopher B. Tully, Nayab F. Habib, Heather Gordish-Dressman, Yi-Wen Chen, Jyoti K. Jaiswal, Terence A. Partridge
Davi A.G. Mázala, James S. Novak, Marshall W. Hogarth, Marie Nearing, Prabhat Adusumalli, Christopher B. Tully, Nayab F. Habib, Heather Gordish-Dressman, Yi-Wen Chen, Jyoti K. Jaiswal, Terence A. Partridge
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Research Article Cell biology Muscle biology

TGF-β–driven muscle degeneration and failed regeneration underlie disease onset in a DMD mouse model

Abstract

Duchenne muscular dystrophy (DMD) is a chronic muscle disease characterized by poor myogenesis and replacement of muscle by extracellular matrix. Despite the shared genetic basis, severity of these deficits varies among patients. One source of these variations is the genetic modifier that leads to increased TGF-β activity. While anti–TGF-β therapies are being developed to target muscle fibrosis, their effect on the myogenic deficit is underexplored. Our analysis of in vivo myogenesis in mild (C57BL/10ScSn-mdx/J and C57BL/6J-mdxΔ52) and severe DBA/2J-mdx (D2-mdx) dystrophic models reveals no defects in developmental myogenesis in these mice. However, muscle damage at the onset of disease pathology, or by experimental injury, drives up TGF-β activity in the severe, but not in the mild, dystrophic models. Increased TGF-β activity is accompanied by increased accumulation of fibroadipogenic progenitors (FAPs) leading to fibro-calcification of muscle, together with failure of regenerative myogenesis. Inhibition of TGF-β signaling reduces muscle degeneration by blocking FAP accumulation without rescuing regenerative myogenesis. These findings provide in vivo evidence of early-stage deficit in regenerative myogenesis in D2-mdx mice and implicates TGF-β as a major component of a pathogenic positive feedback loop in this model, identifying this feedback loop as a therapeutic target.

Authors

Davi A.G. Mázala, James S. Novak, Marshall W. Hogarth, Marie Nearing, Prabhat Adusumalli, Christopher B. Tully, Nayab F. Habib, Heather Gordish-Dressman, Yi-Wen Chen, Jyoti K. Jaiswal, Terence A. Partridge

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Figure 2

Muscles from D2-mdx mice show evidence of muscle degeneration and calcification starting at the onset of disease.

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Muscles from D2-mdx mice show evidence of muscle degeneration and calcif...
(A) Macroscopic images of 14-, 21-, and 38-day-old D2-mdx mice, 38-day-old D2-WT mice, and 38-day-old B10-mdx mice. D2-mdx mice show development of conspicuous pale stripes in the pectoral muscles between 21 and 38 days of age accompanied by similar changes in other muscles (e.g., triceps, black arrowhead) corresponding to areas of calcification identified in sections by alizarin red staining (D). No abnormal changes were seen in either D2-WT or B10-mdx mice (white arrowhead). (B and C) Signs of endomysial fibrosis in and around areas of degeneration in the triceps muscle were identified by second harmonic generation (B) and trichrome stain (C) in muscles of D2-mdx mice at 38 days of age. (D and E) H&E and alizarin red staining of triceps muscle sections from D2-mdx and B10-mdx mice at 14, 21, and 38 days of age. (F and G) Quantification of the percentage of calcified area and centrally nucleated fibers (CNFs) in triceps muscles from B10-mdx and D2-mdx at 21 days and 38 days old. (F) Quantification of percentage of calcification from 21-day-old D2-mdx mice (n = 4), 38-day-old D2-mdx mice (n = 7), and 38-day-old B10-mdx mice (n = 4). (G) Quantification of CNF percentage from 21-day-old D2-mdx mice (n = 4), 38-day-old D2-mdx mice (n = 8), and 38-day-old B10-mdx mice (n = 4). For F and G, data are expressed as mean ± SD. One-way ANOVA with Tukey’s post hoc comparison. **P < 0.01; ***P < 0.001; ****P < 0.0001. Scale bars: 50 μm (B and C), 20 μm (D and E).