Macrophages fine tune satellite cell fate in dystrophic skeletal muscle of mdx mice.

Luca Madaro,Mattia Pelizzola,Francesca De Santa,Federica F Contino,Giuseppe R Diaferia,Alessio Torcinaro,Marina Bouchè,Marco De Bardi,Giulia Imeneo,Pier Lorenzo Puri,Gregory A Cox

doi:10.1371/journal.pgen.1008408

Luca Madaro, Mattia Pelizzola + Show 9 more

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https://doi.org/10.1371/journal.pgen.1008408

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Abstract

Satellite cells (SCs) are muscle stem cells that remain quiescent during homeostasis and are activated in response to acute muscle damage or in chronic degenerative conditions such as Duchenne Muscular Dystrophy. The activity of SCs is supported by specialized cells which either reside in the muscle or are recruited in regenerating skeletal muscles, such as for instance macrophages (MΦs). By using a dystrophic mouse model of transient MΦ depletion, we describe a shift in identity of muscle stem cells dependent on the crosstalk between MΦs and SCs. Indeed MΦ depletion determines adipogenic conversion of SCs and exhaustion of the SC pool leading to an exacerbated dystrophic phenotype. The reported data could also provide new insights into therapeutic approaches targeting inflammation in dystrophic muscles.

Highlights

Duchenne Muscular Dystrophy (DMD) is one of the most severe dystrophies and is caused by the loss of functional dystrophin protein owing to genetic mutations, the sarcolemma becomes fragile and susceptible to muscle damage induced by contraction
Duchenne Muscular Dystrophy (DMD) is one of the most severe dystrophies caused by mutations that lead to the loss of a functional dystrophin protein, a structural protein associated to the muscle fiber membrane
We investigated the role of macrophages (MFs) in regeneration of dystrophic muscles by taking advantage of a transgenic mouse model that allows to transiently deplete macrophages

Summary

Introduction

Duchenne Muscular Dystrophy (DMD) is one of the most severe dystrophies caused by mutations that lead to the loss of a functional dystrophin protein, a structural protein associated to the muscle fiber membrane. Satellite cells (SCs) are bona fide muscle stem cells that are quiescent during homeostasis and are activated in response to acute muscle damage or in chronic degenerative conditions such as DMD [4]. SCs are able to both self-renew, in order to maintain the stem cell pool, and to differentiate into myoblasts that fuse with each other and with surrounding fibers to generate new myofibers or repair the damaged ones [5]. The proper expansion and myogenic commitment of SCs is crucial to efficiently counteract muscle degeneration and maintain the SC pool in dystrophic muscles [6,7]. SCs respond to a large variety of extrinsic signals derived from the regenerative microenvironment that affect muscle stem cell fate. The activity of SCs is supported by specialized cell populations resident in skeletal muscles, such as fibroblasts, fibroadipogenic progenitors (FAPs) [13,14] and vascular cells [15], or recruited from the bloodstream in response to muscle damage, represented by immune cells [16]

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