Muscle contraction is required to maintain the pool of muscle progenitors via YAP and NOTCH during fetal myogenesis

Joana Esteves De Lima,Marie-Ange Bonnin,Delphine Duprez,Carmen Birchmeier

doi:10.7554/elife.15593

Abstract

The importance of mechanical activity in the regulation of muscle progenitors during chick development has not been investigated. We show that immobilization decreases NOTCH activity and mimics a NOTCH loss-of-function phenotype, a reduction in the number of muscle progenitors and increased differentiation. Ligand-induced NOTCH activation prevents the reduction of muscle progenitors and the increase of differentiation upon immobilization. Inhibition of NOTCH ligand activity in muscle fibers suffices to reduce the progenitor pool. Furthermore, immobilization reduces the activity of the transcriptional co-activator YAP and the expression of the NOTCH ligand JAG2 in muscle fibers. YAP forced-activity in muscle fibers prevents the decrease of JAG2 expression and the number of PAX7+ cells in immobilization conditions. Our results identify a novel mechanism acting downstream of muscle contraction, where YAP activates JAG2 expression in muscle fibers, which in turn regulates the pool of fetal muscle progenitors via NOTCH in a non-cell-autonomous manner.

Highlights

IntroductionGrowth and regeneration rely on muscle stem cells. A major goal of muscle research is to understand the signals that regulate the ability of stem cells to self-renew or differentiate.Skeletal muscle formation involves successive and overlapping phases of embryonic, fetal, perinatal and adult myogenesis
Skeletal muscle development, growth and regeneration rely on muscle stem cells
We conclude that the inhibition of muscle contraction leading to rigid or flaccid paralysis reduces the pool of fetal muscle progenitors and increases their propensity to differentiate

Summary

Introduction

Growth and regeneration rely on muscle stem cells. A major goal of muscle research is to understand the signals that regulate the ability of stem cells to self-renew or differentiate.Skeletal muscle formation involves successive and overlapping phases of embryonic, fetal, perinatal and adult myogenesis. Growth and regeneration rely on muscle stem cells. A major goal of muscle research is to understand the signals that regulate the ability of stem cells to self-renew or differentiate. Skeletal muscle formation involves successive and overlapping phases of embryonic, fetal, perinatal and adult myogenesis. The paired homeobox transcription factors, PAX3 and PAX7, define the pool of muscle stem cells during developmental, postnatal and regenerative myogenesis (Gros et al, 2005; Kassar-Duchossoy, 2005; Relaix et al, 2005). Fetal myogenesis depends on PAX7-expressing muscle progenitors and is associated with muscle growth (Hutcheson et al, 2009; Kassar-Duchossoy, 2005; Relaix et al, 2005). Muscle progenitors undergo myogenic differentiation program with the activation of the bHLH Myogenic Regulatory Factors (MRFs), MYF5, MRF4, MYOD, MYOG (Tajbakhsh, 2009). The influence of the mechanical forces for cartilage, joint, and bone development has been previously addressed (Nowlan et al, 2010; Rolfe et al, 2014; Shwartz et al, 2013), the consequence of muscle-induced mechanical load for the development of muscle itself is largely unknown

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