Myf5-Positive Satellite Cells Contribute to Pax7-Dependent Long-Term Maintenance of Adult Muscle Stem Cells

Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Ludwigstraße 43, 61231 Bad Nauheim, Germany.
Cell stem cell (Impact Factor: 22.27). 08/2013; 13(6). DOI: 10.1016/j.stem.2013.07.016
Source: PubMed


Skeletal muscle contains Pax7-expressing muscle stem or satellite cells, enabling muscle regeneration throughout most of adult life. Here, we demonstrate that induced inactivation of Pax7 in Pax7-expressing cells of adult mice leads to loss of muscle stem cells and reduced heterochromatin condensation in rare surviving satellite cells. Inactivation of Pax7 in Myf5-expressing cells revealed that the majority of adult muscle stem cells originate from myogenic lineages, which express the myogenic regulators Myf5 or MyoD. Likewise, the majority of muscle stem cells are replenished from Myf5-expressing myogenic cells during adult life, and inactivation of Pax7 in Myf5-expressing cells after muscle damage leads to a complete arrest of muscle regeneration. Finally, we demonstrate that a relatively small number of muscle stem cells are sufficient for efficient repair of skeletal muscles. We conclude that Pax7 acts at different levels in a nonhierarchical regulatory network controlling muscle-satellite-cell-mediated muscle regeneration.

Download full-text


Available from: Chen Ming Fan, Apr 03, 2014
    • "Additionally, fibro-adipogenic (FAP) cells support muscle repair by promoting the differentiation of other muscle precursor cells [48] [49]. Importantly, the resident population of Pax7+ satellite cells appears to provide the majority of muscle precursor cells necessary for repairing muscle, while other populations contribute fewer cells to regenerating adult muscle under physiological conditions [50] [51] [52] [53] [54]. Satellite cells were originally described based on their location, as they reside outside the sarcolemma, but under the basal lamina [55]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: While changes in muscle protein synthesis and degradation have long been known to contribute to muscle wasting, a body of literature has arisen which suggests that regulation of the satellite cell and its ensuing regenerative program are impaired in atrophied muscle. Lessons learned from cancer cachexia suggest that this regulation is simply not a consequence, but a contributing factor to the wasting process. In addition to satellite cells, evidence from mouse models of cancer cachexia also suggests that non-satellite progenitor cells from the muscle microenvironment are also involved. This chapter in the series reviews the evidence of dysfunctional muscle repair in multiple wasting conditions. Potential mechanisms for this dysfunctional regeneration are discussed, particularly in the context of cancer cachexia.
    Seminars in Cell and Developmental Biology 09/2015; DOI:10.1016/j.semcdb.2015.09.009 · 6.27 Impact Factor
    • "The anti-apoptotic properties of Pax7 cannot be compensated by the closely related Pax3 protein, highlighting the importance of Pax7 in promoting cell survival and in controlling the stem cell populations of adult tissues (Relaix et al., 2006). More recent tissue-specific analyses have provided additional evidence for Pax7 function in the maintenance and regenerative capacity of satellite cells (Gunther et al., 2013; von Maltzahn et al., 2013). The onset of satellite cell differentiation leads to the down-regulation of Pax7 and triggers the expression of myogenin (Zammit et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Brg1 (Brahma-related gene 1) is a catalytic component of the evolutionarily conserved mammalian SWI/SNF ATP-dependent chromatin remodeling enzymes that disrupt histone-DNA contacts on the nucleosome. While the requirement for the SWI/SNF enzymes in cell differentiation has been extensively studied, its role in precursor cell proliferation and survival is not as well defined. Muscle satellite cells constitute the stem cell pool that sustains and regenerates myofibers in adult skeletal muscle. Here, we show that deletion of Brg1 in primary mouse myoblasts derived from muscle satellite cells cultured ex vivo leads to a cell proliferation defect and apoptosis. We determined that Brg1 regulates cell proliferation and survival by controlling chromatin remodeling and activating transcription at the Pax7 promoter, which is expressed during somite development and is required for controlling viability of the satellite cell population. Reintroduction of catalytically active Brg1 or of Pax7 into Brg1-deficient satellite cells rescued the apoptotic phenotype and restored proliferation. These data demonstrate that Brg1 functions as a positive regulator for cellular proliferation and survival of primary myoblasts. Therefore, the regulation of gene expression through Brg1-mediated chromatin remodeling is critical not just for skeletal muscle differentiation but for maintaining the myoblast population as well. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 06/2015; 230(12). DOI:10.1002/jcp.25031 · 3.84 Impact Factor
  • Source
    • "During CTX-induced regeneration in control mice, protein expression of Pax7, a definitive satellite cell marker [24] [25], is highly induced at day 5 with substantially higher levels still detected at day 8 (Fig. 6A), suggesting a marked increase of the satellite cell pool during the peak of regenerative myogenesis, as documented previously [22] [23]. In contrast, this Pax7 response reflecting satellite cell expansion is severely blunted in Bmal1-null, with only slight induction at day 5 and weakly detectable levels at day 8. Analysis of Pax7 transcripts revealed significantly lower levels in Bmal1 -/-mice throughout injury as compared to the WT (Fig. 6B). "

Show more