Macrophage-released ADAMTS1 promotes muscle stem cell activation

Hongqing Du,Michael N Wosczyna,Brian J Feldman,Thomas A Rando,Joonseok Cho,Alisa A Mueller,Chung-Hsuan Shih,Abhishek Aggarwal

doi:10.1038/s41467-017-00522-7

Hongqing Du, Michael N Wosczyna + Show 6 more

Open Access

https://doi.org/10.1038/s41467-017-00522-7

Copy DOI

Abstract

Coordinated activation of muscle stem cells (known as satellite cells) is critical for postnatal muscle growth and regeneration. The muscle stem cell niche is central for regulating the activation state of satellite cells, but the specific extracellular signals that coordinate this regulation are poorly understood. Here we show that macrophages at sites of muscle injury induce activation of satellite cells via expression of Adamts1. Overexpression of Adamts1 in macrophages in vivo is sufficient to increase satellite cell activation and improve muscle regeneration in young mice. We demonstrate that NOTCH1 is a target of ADAMTS1 metalloproteinase activity, which reduces Notch signaling, leading to increased satellite cell activation. These results identify Adamts1 as a potent extracellular regulator of satellite cell activation and have significant implications for understanding the regulation of satellite cell activity and regeneration after muscle injury.

Highlights

IntroductionCoordinated activation of muscle stem cells (known as satellite cells) is critical for postnatal muscle growth and regeneration
Coordinated activation of muscle stem cells is critical for postnatal muscle growth and regeneration
When we examined the muscles of 1-month-old Adamts[1] mice, we did not detect any significant differences in either muscle wet weight or myofiber size compared to sex- and age-matched wild-type littermate controls (Fig. 3e–g), indicating a negligible effect on embryonic and postnatal muscle a progenitors

Summary

Introduction

Coordinated activation of muscle stem cells (known as satellite cells) is critical for postnatal muscle growth and regeneration. We demonstrate that NOTCH1 is a target of ADAMTS1 metalloproteinase activity, which reduces Notch signaling, leading to increased satellite cell activation These results identify Adamts[1] as a potent extracellular regulator of satellite cell activation and have significant implications for understanding the regulation of satellite cell activity and regeneration after muscle injury. T he progressive activation and differentiation of satellite cells is critical for proper skeletal muscle growth and muscle regeneration after injury[1, 2] This cascade is initiated when satellite cells are activated to break quiescence, progress through differentiation, and fuse to nascent or injured muscle fibers[2, 3]. In spite of the apparent canonical role of Notch signaling in the regulation of satellite cell activation, the extracellular triggers that inhibit Notch signaling and promote satellite cells to break quiescence and differentiate are largely unknown

Methods

Results

Conclusion