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

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

doi:10.1172/jci.insight.135703

Davi A.G Mázala, Jyoti K Jaiswal + Show 9 more

Open Access

https://doi.org/10.1172/jci.insight.135703

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Journal: JCI insight	Publication Date: Mar 26, 2020
Citations: 97	License type: cc-by

Affiliation: Children's National

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.

Highlights

Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by mutations that result in the absence of dystrophin protein, a cytoplasmic protein that helps tether the cytoskeletal actin to the extracellular matrix [1, 2]
These features mimic deficits reported in muscles from patients with DMD, indicating the D2-mdx mouse as a pertinent model in which to investigate the inflammatory and degenerative pathology seen in DMD and to delineate the interplay between the muscle degenerative and regenerative processes that drive myogenic deficit in this disease. Using this model, we establish the utility of inhibiting TGF-β activity to ameliorate fibroadipogenic progenitors (FAPs)-mediated fibro-calcified muscle degeneration. We show this inhibition alone is not sufficient to reverse the myogenic deficit, identifying the relevance of the D2-mdx model to investigate the complexity of the downstream effects of TGF-β hyperactivity and for discovery of combinatorial drugs that can simultaneously restrict muscle degeneration and activate myogenesis in dystrophic muscles
Whether the regenerative failure is attributable to degradation of the muscle microenvironment or to the exhaustion of muscle-resident satellite cells is a matter of active debate [16, 17]

Summary

Introduction

Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by mutations that result in the absence of dystrophin protein, a cytoplasmic protein that helps tether the cytoskeletal actin to the extracellular matrix [1, 2]. Despite the ability of skeletal muscle to fully regenerate myofibers, patients with DMD show progressive deposition of fibrous extracellular matrix (ECM), which replaces muscle fibers and severely compromises muscle function [5]. Failed regeneration and ongoing degeneration observed in DMD muscles implicate dysregulation of muscle-resident myogenic and nonmyogenic stem cells. Interactions between these stem cells and inflammatory cells are crucial to efficient muscle regeneration [8, 9].

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