DNA damage signaling mediates the functional antagonism between replicative senescence and terminal muscle differentiation

Latella, Lucia; Dall’Agnese, Alessandra; Boscolo, Francesca S.; Nardoni, Chiara; Cosentino, Marianna; Lahm, Armin; Sacco, Alessandra; Puri, Prem

doi:10.1101/gad.293266.116

Cited by 29 publications

(21 citation statements)

References 44 publications

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“…Lack of expression of dystrophin causes the development of DMD and thus continuous activation of the muscle regenerative program. In our study, spontaneous tumor development occurred in 10% mdx/mTR mice at ~9 months of age (Het to G2), consistent with the low incidence of tumor formation in mdx mice, but with an earlier age of onset, suggesting involvement of disease severity and increased tissue turnover in tumor formation (Chamberlain et al, 2007; Chang et al, 2016; Fernandez et al, 2010; Latella et al, 2017; Sacco et al, 2010). In our study, we employed mice in a C57BL/6 background and compared their tumor phenotype to both C57BL/10 and C57BL/6 × C57BL/10 mixed-background mice utilized in previous studies (Camboni et al, 2012; Fernandez et al, 2010).…”

Section: Discussionsupporting

confidence: 85%

“…It has previously been reported that muscular dystrophy activates DNA damage response pathways (Schmidt et al, 2011; Tichy et al, 2017), and we recently showed that MuSCs from mdx/mTR G2 mice accumulate DNA damage when compared to mdx/mTR Het/G1 mice (Latella et al, 2017). Thus, we assessed whether knockout of p53 in mdx/mTR G2 mice could accumulate further DNA damage and whether this could lead to tissue instability, favoring RMS development.…”

Section: Resultsmentioning

confidence: 84%

“…The mdx mouse, a model for Duchenne muscular dystrophy (DMD), a progressive muscle degenerative disease that places a strong regenerative pressure on the MuSC compartment (Duchenne, 1867; Hoffman et al, 1987), shows an increased incidence of spontaneous RMS development (Chamberlain et al, 2007; Fernandez et al, 2010; Hosur et al, 2012). Increased susceptibility to RMS has been attributed to multiple features of the dystrophic disease, including accumulation of DNA damage, inflammation, and reactive oxygen species (Fanzani et al, 2013; Hanahan and Weinberg, 2000; Latella et al, 2017; Schmidt et al, 2011; Wang et al, 2014). This suggests that a highly regenerative pathological muscle microenvironment is more permissive to tumor development.…”

Section: Introductionmentioning

confidence: 99%

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Muscle Stem Cells Give Rise to Rhabdomyosarcomas in a Severe Mouse Model of Duchenne Muscular Dystrophy

2019

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SUMMARY Most human cancers originate from high-turnover tissues, while low-proliferating tissues, like skeletal muscle, exhibit a lower incidence of tumor development. In Duchenne muscular dystrophy (DMD), which induces increased skeletal muscle regeneration, tumor incidence is increased. Rhabdomyosarcomas (RMSs), a rare and aggressive type of soft tissue sarcoma, can develop in this context, but the impact of DMD severity on RMS development and its cell of origin are poorly understood. Here, we show that RMS latency is affected by DMD severity and that muscle stem cells (MuSCs) can give rise to RMS in dystrophic mice. We report that even before tumor formation, MuSCs exhibit increased self-renewal and an expression signature associated with RMSs. These cells can form tumorspheres in vitro and give rise to RMSs in vivo. Finally, we show that the inflammatory genes Ccl11 and Rgs5 are involved in RMS growth. Together, our results show that DMD severity drives MuSC-mediated RMS development.

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Section: Discussionsupporting

confidence: 85%

Section: Resultsmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

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Muscle Stem Cells Give Rise to Rhabdomyosarcomas in a Severe Mouse Model of Duchenne Muscular Dystrophy

2019

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“…This exposure to ROS throughout life combined with a decline in their antioxidant capacity during ageing ( Sullivan-Gunn and Lewandowski, 2013 ; Fulle et al, 2005 ) makes geriatric satellite cells particularly vulnerable to accumulation of genomic and mitochondrial DNA mutations, and as a consequence, to mitochondrial dysfunction and genomic instability. Geriatric satellite cells have been shown to have elevated p38α MAP kinase activity ( Cosgrove et al, 2014 ; Bernet et al, 2014 ) and defective autophagy leading to mitochondrial dysfunction, excessive ROS levels ( García-Prat et al, 2016 ), with increased DNA damage ( García-Prat et al, 2016 ; Sinha et al, 2014 ) and senescence ( Sousa-Victor et al, 2014 ; Latella et al, 2017 ). In view of the Pitx2/3 -mutant phenotype ( Figure 7—figure supplement 1 ), and in correlation with observations on hyper-homo-cysteinemic mice ( Veeranki et al, 2015 ), we propose that Pitx2/3 mutants may represent a useful model of premature muscle ageing.…”

Section: Discussionmentioning

confidence: 99%

The role of Pitx2 and Pitx3 in muscle stem cells gives new insights into P38α MAP kinase and redox regulation of muscle regeneration

L’honoré

Commère

Négroni

et al. 2018

eLife

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Skeletal muscle regeneration depends on satellite cells. After injury these muscle stem cells exit quiescence, proliferate and differentiate to regenerate damaged fibres. We show that this progression is accompanied by metabolic changes leading to increased production of reactive oxygen species (ROS). Using Pitx2/3 single and double mutant mice that provide genetic models of deregulated redox states, we demonstrate that moderate overproduction of ROS results in premature differentiation of satellite cells while high levels lead to their senescence and regenerative failure. Using the ROS scavenger, N-Acetyl-Cysteine (NAC), in primary cultures we show that a physiological increase in ROS is required for satellite cells to exit the cell cycle and initiate differentiation through the redox activation of p38α MAP kinase. Subjecting cultured satellite cells to transient inhibition of P38α MAP kinase in conjunction with NAC treatment leads to their rapid expansion, with striking improvement of their regenerative potential in grafting experiments.

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“…This phenomenon is termed as replicative senescence and is associated with telomere shortening over the course of continuous replication, which can activate DNA damage response (DDR). DDR is characterized by p53‐mediated induction of p21, a protein responsible for cell‐cycle arrest (Hewitt et al, 2012; Fumagalli et al, 2014; Hills and Diffley, 2014; Latella et al, 2017). However, senescence can also be induced prematurely apart from the conventional replicative senescence by various genotoxic stress such as ROS, DNA damage, or by the action of an oncogene such as Myc or Ras (Serrano et al, 1997; Grandori et al, 2003; Campaner et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Hyaluronan‐binding protein 1 (HABP1) overexpression triggers induction of senescence in fibroblasts cells

Vikramdeo

Saha

Dutta

et al. 2020

Cell Biology International

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Hyaluronan-binding protein 1 (HABP1), a multi-compartmental, multi-functional protein has a wide range of functions, which can be attributed to its ability to associate with a variety of cellular ligands. Earlier we have reported that HABP1 overexpression in rat normal fibroblasts (F-HABP07) shows chronic generation of reactive oxygen species (ROS), induction of autophagy, and apoptosis. However, a significant proportion of cells remained viable after the majority went through apoptosis from 60 to 72 h. In this study, an attempt has been made to delineate the cellular events in the declined population of surviving cells. It has been elucidated here that, these cells at later time points of growth, that is, 72 and 84 h, not only appeared to shrink but also are devoid of autophagic vacuoles and displayed polyploidy. F-HABP07 cells exhibited an altered cytoskeletal structure from their parental cell line F111, assumed to be caused upon inhibition of actin polymerization and decrease in IQ motif-containing GTPase activating protein 1 (IQGAP1), a key protein associated with maintenance of cytoskeletal integrity. Enhanced expression and nuclear localization of AKT observed in F-HABP07 cells appears to be contributing toward the maintenance of high ROS levels in these cells and also potentially modulating the IQGAP1 activity. These observations, in fact have been considered to result in sustained DNA damage, which then leads to increased expression of p53 and activation of p21 and carry out the cellular events responsible for senescence. Subsequent assessment of the presence of positive β-gal staining and enhanced expression of p16 INK4a in F-HABP07, confirmed that HABP1 overexpressing fibroblasts undergo senescence.

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DNA damage signaling mediates the functional antagonism between replicative senescence and terminal muscle differentiation

Cited by 29 publications

References 44 publications

Muscle Stem Cells Give Rise to Rhabdomyosarcomas in a Severe Mouse Model of Duchenne Muscular Dystrophy

Muscle Stem Cells Give Rise to Rhabdomyosarcomas in a Severe Mouse Model of Duchenne Muscular Dystrophy

The role of Pitx2 and Pitx3 in muscle stem cells gives new insights into P38α MAP kinase and redox regulation of muscle regeneration

Hyaluronan‐binding protein 1 (HABP1) overexpression triggers induction of senescence in fibroblasts cells

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