Androgen receptor in satellite cells is not essential for muscle regenerations

Hiroshi Sakai,Takahiko Sato,Yuuki Imai,Motoi Kanagawa,So-Ichiro Fukada,Martin Michaelis

doi:10.1017/exp.2020.14

Hiroshi Sakai, Takahiko Sato + Show 4 more

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https://doi.org/10.1017/exp.2020.14

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Abstract

AbstractThe anabolic effects of androgen on skeletal muscles are thought to be mediated by androgen receptor (AR). Although multiple studies concerning the effects of AR in males have been performed, the molecular mechanisms of AR in skeletal muscles remain unclear. Here we first confirmed that satellite cells from mouse hindlimb muscles express AR. We then generated satellite cell-specific AR knockout mice using Pax7CreERT2 and ARL2/Y mice to test whether AR in satellite cells is necessary for muscle regeneration. Surprisingly, we found that muscle regeneration was compromised in both Pax7CreERT2(Fan)/+ control mice and Pax7CreERT2(Fan)/+;ARL2/Y mice compared to ARL2/Y mice. However, Pax7CreERT2(Gaka)/+;ARL2/Y;R26tdTomato/+ mice showed no significant differences between control and mutant muscle regeneration. These findings indicate that AR in satellite cells is not essential for muscle regeneration. We propose that Pax7CreERT2(Fan)/+ control mice should be included in all experiments, because these mice negatively affect the muscle regeneration and show the mild regeneration phenotype.

Highlights

Regenerative capacity of adult skeletal muscles is mediated by muscle stem cells, termed satellite cells (Lepper et al, 2011; Murphy et al, 2011; Sambasivan et al, 2011), which express the transcription factor Pax7 (Seale et al, 2000)
In Pax7CreERT2(Fan)/+;ARL2/Y mice having conditional androgen receptor (AR) deletion, AR mRNA levels in FACS-isolated satellite cells were decreased relative to control (Pax7+/+; ARL2/Y) mice (Figure 1B)
Upon muscle injury, the number of Pax7+ cells decreased by similar amounts in Pax7CreERT2(Fan)/+ control mice and Pax7CreERT2(Fan)/+;ARL2/Y mice at 5 dpi (Figure 1C-E), while Pax7CreERT2(Fan)/+ control mice showed slightly delayed muscle regeneration at 14 dpi (Figure 1F-H)

Summary

Introduction

Regenerative capacity of adult skeletal muscles is mediated by muscle stem cells, termed satellite cells (Lepper et al, 2011; Murphy et al, 2011; Sambasivan et al, 2011), which express the transcription factor Pax (Seale et al, 2000). Sex hormones, including androgens, are thought to play an important role in satellite cell function during muscle development and repair after injury (Kim et al, 2016). The molecular mechanisms by which androgen receptor (AR), a member of the nuclear receptor superfamily, might regulate satellite cells remain poorly understood. There are no studies that examined whether AR plays important roles in satellite cells during muscle regeneration using satellite cells-specific knock-out mice of AR in adults

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