Distinct metabolic states govern skeletal muscle stem cell fates during prenatal and postnatal myogenesis.

Francesca Pala,Miria Ricchetti,Shahragim Tajbakhsh,Daniela Di Girolamo,Siham Yennek,Sébastien Mella,Laurent Chatre

doi:10.1242/jcs.212977

Abstract

ABSTRACTDuring growth, homeostasis and regeneration, stem cells are exposed to different energy demands. Here, we characterise the metabolic pathways that mediate the commitment and differentiation of mouse skeletal muscle stem cells, and how their modulation can influence the cell state. We show that quiescent satellite stem cells have low energetic demands and perturbed oxidative phosphorylation during ageing, which is also the case for cells from post-mortem tissues. We show also that myogenic fetal cells have distinct metabolic requirements compared to those proliferating during regeneration, with the former displaying a low respiration demand relying mostly on glycolysis. Furthermore, we show distinct requirements for peroxisomal and mitochondrial fatty acid oxidation (FAO) in myogenic cells. Compromising peroxisomal but not mitochondrial FAO promotes early differentiation of myogenic cells. Acute muscle injury and pharmacological block of peroxisomal and mitochondrial FAO expose differential requirements for these organelles during muscle regeneration. Taken together, these observations indicate that changes in myogenic cell state lead to significant alterations in metabolic requirements. In addition, perturbing specific metabolic pathways impacts on myogenic cell fates and the regeneration process.

Highlights

Stem cells in different tissues and organs occupy quiescent or proliferative states in diverse microenvironments
To determine whether different quiescent states have different metabolic requirements, we examined the gene expression profiles of satellite cells isolated from mice aged 6–8 weeks and 24–26 months by performing microarray analysis
Post-mortem satellite cells showed an enrichment in the pathways related to the electron transport chain (ETC) and mitochondrial functions, including the RNA polymerase I, RNA pol III and mitochondrial transcription subset (Fig. 1A), suggesting that mitochondrial transcripts are more stable under conditions of extreme stress. These findings were confirmed by real-time quantitative PCR (RT-qPCR) analysis using satellite cells isolated by fluorescence-activated cell sorting (FACS) from Tg:Pax7nGFP mice (Sambasivan et al, 2009), where we examined numerous key enzymes involved in the main metabolic pathways

Summary

Introduction

Stem cells in different tissues and organs occupy quiescent or proliferative states in diverse microenvironments. Skeletal muscle satellite (stem) cells are located between the basement membrane and plasmalemma of muscle fibres and are crucial for skeletal muscle growth and regeneration (Comai and Tajbakhsh, 2014; Lepper et al, 2011; Murphy et al, 2011; Sambasivan et al, 2011). They are quiescent under homeostatic conditions in adults and are activated upon muscle injury when they re-enter the cell cycle; they proliferate and differentiate into myoblasts, which subsequently fuse to form muscle fibres; and they self-renew. A third myogenic regulatory factor, myogenin, is expressed in cells undergoing differentiation (Comai and Tajbakhsh, 2014)

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Conclusion