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Cited by 512Muscle Physiology and DisordersNeurogenetic and Muscular Disorders ResearchTelomeres, Telomerase, and Senescence

Short Telomeres and Stem Cell Exhaustion Model Duchenne Muscular Dystrophy in mdx/mTR Mice

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Sacco, Alessandra, Mourkioti, Foteini, Tran, Rose, Choi, Jinkuk, Llewellyn, Michael, Kraft, Peggy, Shkreli, Marina, Delp, Scott +3 more·2010·Cell
DOI 10.1016/j.cell.2010.11.039PMC PMC3025608
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Abstract

Summary In Duchenne muscular dystrophy (DMD), dystrophin mutation leads to progressive lethal skeletal muscle degeneration. For unknown reasons, dystrophin deficiency does not recapitulate DMD in mice (mdx), which have mild skeletal muscle defects and potent regenerative capacity. We postulated that human DMD progression is a consequence of loss of functional muscle stem cells (MuSC) and the mild mouse mdx phenotype results from greater MuSC reserve fueled by longer telomeres. We report that mdx mice lacking the RNA component of telomerase (mdx/mTR) have shortened telomeres in muscle cells and severe muscular dystrophy that progressively worsens with age. Muscle wasting severity parallels a decline in MuSC regenerative capacity, and is ameliorated histologically by transplantation of wild-type MuSC. These data show that DMD progression results in part from a cell-autonomous failure of MuSC to maintain the damage-repair cycle initiated by dystrophin deficiency. The essential role of MuSC function has therapeutic implications for DMD.

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Claims the paper makes

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  • Findingown data

    The severity of muscle wasting parallels a decline in the regenerative capacity of muscle stem cells.

    “Muscle wasting severity parallels a decline in MuSC regenerative capacity”
    Quote in the paperSubstantial claim
  • Findingown data

    In undamaged wild-type mice, only 0.4±0.2% of muscle stem cells were BrdU positive.

    “In WT mice in undamaged conditions, only 0.4±0.2% of MuSC were BrdU+ (Fig. 4A–B)”
    Quote in the paperNot a substantial claim
  • Findingown data

    In 8-week-old mice, diaphragm and tibialis anterior mdx/mTRG2 muscles show an increase in weight relative to total body weight.

    “In 8 week old mice, the diaphragm and tibialis anterior mdx/mTRG2 muscles exhibit an increase in weight relative to total body weight (Fig 3B)”
    Quote in the paperNot a substantial claim
  • Findingreasoning

    Heterozygous mdx/mTRHet mice show increased creatine kinase levels with age.

    “Heterozygous mdx/mTRHet mice with increased age show increased CK levels, presumably due to slower progression of the disease (Fig. S1A).”
    Quote in the paperNot a substantial claim
  • Findingnone given

    Muscle histology from mTRG2 control mice is indistinguishable from wild-type mice.

    “Importantly, muscle histology from mTRG2 control mice is indistinguishable from WT mice.”
    Quote in the paperSubstantial claim
  • May combine two claims. 49
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Findingown data

    The weight of control testis tissue does not change significantly among genotypes, indicating that tissue atrophy is specific to muscles.

    “The weight of control testis tissue, a high proliferative organ, does not change significantly among genotypes, indicating that the tissue atrophy is specific to muscles (Fig. S5).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Muscle performance worsens with age, as 24-week-old mdx/mTRG2 mice barely run at all (1.1±0.6 min).

    “Muscle performance further worsens with age, as 24 week old mdx/mTRG2 mice barely run at all (1.1±0.6min)(Figs. 1C and S1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In undamaged mdx/mTRHet mice, 2.5±1.4% of muscle stem cells are BrdU positive, higher than in wild-type mice.

    “In undamaged mdx/mTRHet mice, 2.5±1.4% of MuSC are BrdU+, which is higher than WT mice, consistent with ongoing tissue regeneration due to dystrophin deficiency.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    mdx/mTR mice develop severe muscular dystrophy that becomes progressively worse with age.

    “severe muscular dystrophy that progressively worsens with age”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    When controlled for total body weight, all genotypes show a progressive decrease in weight with age, but the drop is accelerated in mdx/mTRG2 muscles after 60 weeks.

    “When controlled for total body weight, all genotypes exhibit a progressive decrease in weight with age, but the drop is accelerated in mdx/mTRG2 muscles after 60 weeks.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    mdx/mTRG2 mice have reduced life-span, beginning to die at 48 weeks of age, while mdx/mTRHet mice do not differ from wild-type animals.

    “Kaplan-Meyer survival analyses show that mdx/mTRG2 mice have reduced life-span, starting to die at 48 weeks of age, while mdx/mTRHet do not show a difference compared to WT animals (Fig. 3C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    By 60 weeks of age, creatine kinase levels decline in mdx/mTRG2 mice, matching the pattern in DMD patients where levels peak at 1-6 years and then decrease with age.

    “However, by 60 weeks of age, CK levels decline in mdx/mTRG2 mice (Fig. S1A), consistent with CK levels in DMD patients which peak at 1–6 years of age when active muscle degeneration is occurring, and then decrease with age, as muscle tissue is progressively lost (Zatz et al., 1991).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zatz et al., 1991 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Spleen and testis, two highly proliferative organs, are not affected in the generations analyzed, arguing against effects from Terc absence alone and in favor of a muscle-specific etiology.

    “Analyses of spleen and testis reveal that these two high proliferative organs are not affected in the generations analyzed (Fig. S5), which argues against the possibility that the effects observed are due to the absence of Terc alone and in favor of a muscle-specific etiology.”
    Quote in the paperSubstantial claim

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    Findingown data

    Lateral gastrocnemius twitch force, tetanic force, and tetanic tension are markedly decreased in mdx/mTRG1 mice and further decreased in mdx/mTRG2 mice compared with wild-type, mdx/mTRHet, and mTRG2 controls.

    “Lateral gastrocnemius muscle twitch force, tetanic force and tetanic tension are markedly decreased in mdx/mTRG1 and further decrease in mdx/mTRG2 mice, compared to control WT, mdx/mTRHet, and mTRG2 mice (Figs. 1F–G and S1D), providing direct evidence for progressively severe muscle weakness.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The percentage of desmin-positive cells is not significantly different between mdx/mTRHet (47±8%) and mdx/mTRG2 myofibers (40±21%), indicating no impairment in mdx/mTRG2 satellite cells transitioning to myoblasts.

    “The percentage of desmin+ cells is not significantly different between mdx/mTRHet (47±8%) and mdx/mTRG2 myofibers (40±21%), indicating that there is no impairment in mdx/mTRG2 satellite cells to transition to myoblasts (Fig. 6C–D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The percentage of centrally nucleated myofibers is increased in mdx/mTRHet mice (63±4%) relative to wild-type (0.7±0.1%), and further increased in mdx/mTRG1 and mdx/mTRG2 muscles (90±1%).

    “Histologically, the percentage of centrally nucleated myofibers, a hallmark of muscle regeneration, is increased in mdx/mTRHet mice (63±4%) relative to WT (0.7±0.1%), but is further increased in mdx/mTRG1 and mdx/mTRG2 muscles (90±1%)(Figs. 1H and 2A)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Muscle stem cells from mdx/mTRG1 (1.4±0.3%) and mdx/mTRG2 (1.3±0.2%) mice show markedly reduced BrdU incorporation without notexin damage, and this does not significantly increase after injury in mdx/mTRG1 (1.6±0.1%) and mdx/mTRG2 (2.5±0.4%) mice.

    “In contrast, MuSC from mdx/mTRG1 (1.4±0.3%) and mdx/mTRG2 (1.3±0.2%) mice exhibit markedly reduced BrdU incorporation in the absence of notexin damage (Fig. 4A–B), which does not significantly increase upon injury in mdx/mTRG1 (1.6±0.1%) and mdx/mTRG2 mice (2.5±0.4%), indicating a severe defect in MuSC proliferation prior to and in response to tissue damage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    End-to-end chromosome fusions were detected in metaphase spreads of myoblasts from mdx/mTRG1 and mdx/mTRG2 mice, indicating that telomere shortening in these cells leads to genomic instability.

    “In addition, in metaphase spreads of myoblasts from mdx/mTRG1 and mdx/mTRG2 mice end-to-end chromosome fusions were detected (Fig. 5A, arrows), indicating that the telomere shortening in these cells leads to genomic instability.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The reduction in satellite cell proliferation persists with age; at 60 weeks, satellite cells from mdx/mTRG2 mice produce only 40% as many cells (307±47) as controls (707±37).

    “The reduction in satellite cell proliferation persists with age; at 60 weeks satellite cells from mdx/mTRG2 mice give rise only to 40% as many cells (307±47) as controls (707±37)(Fig. 6B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Control mTRG2 mice are indistinguishable from wild-type mice in Evans Blue Dye uptake, confirming that absence of telomerase activity alone is not sufficient to trigger skeletal muscle damage.

    “Control mTRG2 mice are indistinguishable from WT mice, confirming that the absence of telomerase activity per se is not sufficient to trigger skeletal muscle damage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After notexin injury, wild-type muscle stem cells are activated, enter the cell cycle, and 8.6±2.9% are BrdU positive.

    “However, upon notexin injury, WT MuSC are activated, enter the cell cycle, and 8.6±2.9% are BrdU+ (Fig. 4A–B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Histological analyses of diaphragm and gastrocnemius muscles from 8-week-old mdx/mTRG2 mice show increased myofiber diameter heterogeneity, mononuclear cellular infiltration, necrosis, and altered tissue structure relative to age-matched controls.

    “Further histological analyses of diaphragm and gastrocnemius muscles from 8 week old mdx/mTRG2 mice reveal a marked increase in myofiber diameter heterogeneity, mononuclear cellular infiltration, necrosis and overall altered tissue structure relative to age-matched controls (Fig. 2A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Premature MuSC differentiation and reduced MuSC numbers per myofiber at disease onset were ruled out as causes of the severe muscle wasting phenotype in mdx/mTRG2 mice.

    “We ruled out other possible stem cell etiologies such as premature MuSC differentiation or a reduction in MuSC numbers per myofiber at the time of disease onset.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MuSC from mdx/mTRG2 mice have severe proliferation defects both in vitro and in vivo.

    “Instead, we determined both in vitro and in vivo that the MuSC from mdx/mTRG2 mice suffer from severe defects in proliferation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Three weeks after transplantation into irradiated Tibialis Anterior muscles of mdx/mTRG2 mice, WT MuSC contributed to an average of 299±29 GFP+ myofibers, while mdx/mTRG2 MuSC contributed to 118±17 GFP+ myofibers.

    “Three weeks post transplantation, WT MuSC efficiently engrafted into recipient muscles, contributed to an average of 299±29 GFP+ myofibers (Figs. 7E–F and S7F–J), while mdx/mTRG2 MuSC contributed to substantially lower numbers of GFP+ myofibers, 118±17 (Fig. 7E–F and S7A–E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    When WT MuSC are transplanted into dystrophic mouse muscles, minimal fibrosis is observed, whereas fibrosis is extensive when proliferation-impaired mdx/mTRG2 MuSC are transplanted.

    “Here we observe that when WT MuSC are transplanted into dystrophic mouse muscles, minimal fibrosis is observed, whereas fibrosis is extensive when proliferation impaired mdx/mTRG2 MuSC are transplanted.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Muscle stem cells isolated from mdx/mTRG2 mice were significantly impaired in engraftment capacity, contributing to substantially lower numbers of myofibers (81±22).

    “Conversely, MuSC isolated from mdx/mTRG2 mice were significantly impaired in their engraftment capacity, contributing to substantially lower numbers of myofibers, 81±22 (Fig. 7C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In muscle regions injected with WT MuSC, inflammatory infiltration was substantially reduced compared to mdx/mTRG2 MuSC injection, with fewer CD45+ cells and improved tissue architecture.

    “Further histological analysis revealed that the amount of inflammatory infiltration is substantially reduced in the muscle region into which the WT MuSC were injected, compared to mdx/mTRG2, as evidenced by the low numbers of CD45+ hematopoietic cells and overall improvement in tissue architecture apparent in H&E sections (Fig. S7K–L).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In vivo, mdx/mTRG2 MuSC showed reduced division by BrdU labeling, smaller revertant clone sizes, inability to respond to injury, and markedly reduced engraftment after transplantation.

    “In vivo, MuSC exhibited reduced division (BrdU labeling), smaller revertant clone sizes, inability to respond to injury, and markedly reduced engraftment upon transplantation into mice.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Telomerase maintains telomere length by adding telomere repeats to chromosome ends, ensuring their proper replication.

    “Telomere length is maintained by the enzyme telomerase, which adds telomere repeats to chromosome ends ensuring their proper replication (Greider and Blackburn, 1985).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Greider and Blackburn, 1985

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    Premisecitation

    Duchenne muscular dystrophy is caused by a mutation in the dystrophin gene.

    “Duchenne Muscular Dystrophy (DMD) is a devastating muscle degenerative disease caused by a mutation in dystrophin (Hoffman et al., 1987)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hoffman et al., 1987 source

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Loss of dystrophin makes the sarcolemma more fragile, causing injury even under mild stress.

    “Absence of dystrophin results in increased fragility of the sarcolemma, leading to injury in the presence of even mild stress (Petrof et al., 1993).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Petrof et al., 1993 source

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Recent studies support and extend the earlier finding that DMD myoblasts have impaired replicative potential and suggest that telomere shortening is common in dystrophic human muscle cells with age and correlates with limited ability to regenerate DMD tissue after transplant.

    “Recent studies support and extend these early findings that myoblasts from DMD have impaired replicative potential and suggest that telomere shortening is a common feature of dystrophic human muscle cells with increasing age and correlates with their limited ability to regenerate DMD tissues upon transplant (Mouly et al., 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mouly et al., 2005 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A 14-fold greater telomere shortening has been reported in DMD patients compared with healthy individuals.

    “Indeed, a 14-fold greater shortening of telomeres in DMD patients relative to healthy individuals has been reported (Decary et al., 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Decary et al., 2000 source

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    Premisecitation

    When telomerase is insufficient, cell proliferation causes progressive telomere shortening and eventually replicative senescence as end-protection fails at some short telomeres.

    “Cell proliferation in settings of insufficient telomerase results in progressive telomere shortening, ultimately leading to replicative senescence as chromosome end-protection is compromised at a subset of short telomeres (Rodier et al., 2005; Sherr and DePinho, 2000).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Rodier et al., 2005 source

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    • cites Sherr and DePinho, 2000 source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Dystrophin is a cytoskeletal protein required for membrane stability in multinucleated skeletal muscle myofibers.

    “a cytoskeletal protein essential for the stability of the membrane of multinucleated myofibers in skeletal muscle (Durbeej and Campbell, 2002)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Durbeej and Campbell, 2002

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DMD patients experience progressive muscle function loss that leads to paralysis and death in the third decade of life.

    “DMD patients suffer from progressive loss of muscle function, leading to paralysis and death in the third decade of life (Emery, 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Emery, 2002 source

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    Premisecitation

    Human DMD myoblasts showed a severe in vitro proliferation deficit that worsened with patient age, yielding only 5% of the normal number of myoblasts per gram of muscle, and the remaining myoblasts had severely impaired proliferative potential.

    “Human DMD myoblasts exhibited a severe proliferation deficit in vitro that became more pronounced with patient age, resulting in a yield of myoblasts per gram muscle of 5% of normal, and the proliferative potential of the remaining myoblasts was severely impaired.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Blau et al., 1983 source

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    • cites Webster and Blau, 1990

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    Premisecitation

    Earlier work by the authors suggested that muscle cells from DMD patients have reduced regenerative capacity due to replicative aging.

    “More than two decades ago, before the cloning of the DMD gene, we obtained data that suggested that muscle cells in DMD patients have diminished regenerative capacity as a consequence of replicative aging (Blau et al., 1983; Webster and Blau, 1990).”
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    • cites Blau et al., 1983 source

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    • cites Webster and Blau, 1990

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    Premisecitation

    Telomere shortening accompanies aging in mitotically active human tissues with high turnover, including blood, liver, skin, testis, and kidneys.

    “Telomere shortening also accompanies aging of mitotically active human tissues with high turnover, including blood, liver, skin, testis, and kidneys (Aikata et al., 2000; Friedrich et al., 2000; Lindsey et al., 1991; Takubo et al., 2000; Vaziri et al., 1993).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Aikata et al., 2000 source

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    • cites Friedrich et al., 2000 source

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    • cites Lindsey et al., 1991 source

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisereasoning

    In DMD, repeated myofiber damage creates a continuous demand for regeneration, and muscle tissue is eventually replaced by fibrosis, calcium deposits, and adipose tissue.

    “In DMD, unrelenting, recurrent myofiber damage elicits a constant need for regeneration. Eventually, muscle tissue is supplanted by fibrosis, calcium deposits and adipose accumulation that coincides with clinical manifestations.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: In DMD, repeated myofiber damage creates a continuous demand for regeneration, and muscle tissue is eventually replaced by fibrosis, calcium deposits, and adipose tissue.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Telomeres are DNA repeats that protect chromosome ends from recombination, fusion, and degradation that would cause genomic instability.

    “Telomeres are DNA repeats that protect chromosome ends from illicit recombination, fusion, and degradation leading to genomic instability (Palm and de Lange, 2008).”
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    • cites Palm and de Lange, 2008 source

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    Premisecitation

    The proliferative defect in DMD myoblasts did not segregate with the X chromosome in clones from doubly heterozygous carriers for DMD and a G6PD variant, indicating dependence on additional factors.

    “However, this proliferative defect did not segregate with the X-chromosome in studies of myoblast clones from doubly heterozygous carriers for two X-linked loci, DMD and a Mediterranean histologically detectable heat-labile variant of G6PD, and was therefore dependent on additional factors (Webster et al., 1986).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Webster et al., 1986 source

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Skeletal muscle has substantial regenerative capacity because of adult muscle stem cells, also called satellite cells, which are important for postnatal muscle growth and repair.

    “skeletal muscle harbors considerable regenerative capacity due to the presence of adult muscle stem cells (MuSC), also known as satellite cells, which play a major role in postnatal muscle growth and repair (Collins et al., 2005; Cornelison et al., 2004; Kuang et al., 2007; Montarras et al., 2005; Sacco et al., 2008).”
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    • cites Collins et al., 2005 source

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    • cites Cornelison et al., 2004 source

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    • cites Kuang et al., 2007 source

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  • May combine two claims.

    Premisecitation

    The mdx mouse, the most widely used DMD model, has only a mild dystrophic phenotype even though it lacks functional dystrophin due to a point mutation.

    “The most widely used animal model for DMD, the mdx mouse, exhibits only a mild dystrophic phenotype, although like DMD patients, it lacks functional dystrophin due to a point mutation in the dystrophin gene (Bulfield et al., 1984; Hoffman et al., 1987; Ryder-Cook et al., 1988).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bulfield et al., 1984 source

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    • cites Hoffman et al., 1987 source

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    • cites Ryder-Cook et al., 1988 source

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  • May combine two claims.

    Premisecitation

    Humans have relatively short telomeres of about 5-15 kilobases, whereas inbred laboratory mice typically have telomeres longer than 40 kilobases.

    “Humans have relatively short telomeres of ~5–15 kilobases in comparison to inbred strains of laboratory mice which have telomeres that are typically >40 kilobases (Kipling and Cooke, 1990).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kipling and Cooke, 1990 source

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  • May combine two claims.

    Premisecitation

    mdx mouse muscles undergo repeated degeneration and regeneration like DMD patients, but for unknown reasons the mice show only transient weakness and never the profound strength loss and death seen in DMD patients.

    “Muscles of mdx mice, like those in DMD patients, undergo repeated cycles of degeneration and regeneration, but for unknown reasons the mice exhibit only transient muscle weakness and never exhibit the profound loss of muscle strength and death observed in DMD patients (DiMario et al., 1991; Straub et al., 1997).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites DiMario et al., 1991 source

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    • cites Straub et al., 1997 source

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  • May combine two claims.

    Interpretationown data

    The dystrophic phenotype is generated by the combination of dystrophin deficiency causing muscle degeneration and progressive exhaustion of functional muscle stem cells.

    “Together, theses results indicate that the combination of the structural defect of dystrophin deficiency that leads to muscle degeneration together with the progressive exhaustion of functional MuSC generates the dystrophic phenotype.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: In DMD, repeated myofiber damage creates a continuous demand for regeneration, and muscle tissue is eventually replaced by fibrosis, calcium deposits, and adipose tissue.

  • May combine two claims.

    Premisecitation

    Telomerase knockout mice have short dysfunctional telomeres that severely impair progenitor cell function in actively renewing tissues, causing atrophy and reduced regenerative potential, while quiescent low-turnover tissues such as muscle are unaffected.

    “In agreement with these findings, studies of telomerase knockout mice revealed short dysfunctional telomeres that profoundly impaired progenitor cell function in actively renewing tissues leading to atrophy and reduced regenerative potential, whereas more quiescent low-turnover tissues such as muscle were unaffected (Allsopp et al., 2003; Lee et al., 1998; Rudolph et al., 1999).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Allsopp et al., 2003 source

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    • cites Lee et al., 1998 source

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    • cites Rudolph et al., 1999 source

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  • May combine two claims.

    Interpretationcitation

    The 5% signal-free end frequency in mdx/mTRG1 and mdx/mTRG2 mice is not seen even in highly proliferative organs until later generations in Terc-deficient mice, indicating that this increase is not due to Terc absence alone.

    “The 5% frequency of SFE seen in mdx/mTRG1 and mdx/mTRG2 mice is not detected even in highly proliferative organs until later generations in mice lacking Terc (Blasco et al., 1997), providing evidence that this increased frequency is not due to Terc absence alone.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Blasco et al., 1997 source

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  • May combine two claims.

    Interpretationcitation

    In humans, DMD begins with the genetic defect but progresses into exhaustion of cells with regenerative potential.

    “These findings support the hypothesis that in humans, DMD is initiated by the genetic defect, but as suggested by our earlier findings (Blau et al., 1983; Webster et al., 1986) develops progressively into an exhaustion of cells with regenerative potential.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Blau et al., 1983 source

      Not checked in the free run.

    • cites Webster et al., 1986 source

      Not checked in the free run.

    • Rests on an assumption: In DMD, repeated myofiber damage creates a continuous demand for regeneration, and muscle tissue is eventually replaced by fibrosis, calcium deposits, and adipose tissue.

  • May combine two claims.

    Interpretationown data

    The progressive creatine kinase elevation in mdx/mTRG1 and mdx/mTRG2 mice suggests that muscle damage worsened across generations, implicating telomere attrition as a cooperating factor with dystrophin deficiency in disease manifestation.

    “The progressive elevation of CK seen in mdx/mTRG1 and mdx/mTRG2 animals suggests that muscle damage deteriorated with successive generations, implicating telomere attrition as a cooperating factor with dystrophin deficiency in disease manifestation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Signal-free ends represent chromosome ends with the shortest telomeres and correlate with increased chromosome fusions and tissue dysfunction in telomerase knockout mice.

    “SFEs represent chromosome ends with the shortest telomeres and correlate with and increased incidence of chromosome fusions and tissue dysfunction in vivo in telomerase knockout mice (Chang et al., 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Chang et al., 2004 source

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  • May combine two claims.

    Interpretationown data

    DMD is a multifactorial process caused by both a structural defect of the tissue and progressive exhaustion of its regenerative potential.

    “Our results indicate that DMD, a muscle degenerative disease, is the result of a multifactorial process, due to both a structural defect of the tissue and to progressive exhaustion of its regenerative potential.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: A longstanding enigma is why humans with a dystrophin mutation suffer from severe muscle wasting whereas mice with the same mutation do not.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Muscle stem cells were isolated by FACS to greater than 90% purity for all genotypes.

    “MuSC were then isolated by FACS to >90% purity for all genotypes (Fig. S4), as previously described (Sacco et al., 2008)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sacco et al., 2008 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Telomerase plays a crucial role in self-renewal of adult stem cells in high-turnover tissues such as blood, liver, skin, and testis.

    “The generation of mouse models lacking telomerase activity, TERT and Terc knockout mice (Blasco et al., 1997; Liu et al., 2000) previously resulted in the demonstration that telomerase plays a crucial role in self-renewal of adult stem cells in high turnover tissues such as blood, liver, skin and testis (Allsopp et al., 2003; Lee et al., 1998).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Blasco et al., 1997 source

      Not checked in the free run.

    • cites Liu et al., 2000 source

      Not checked in the free run.

    • cites Allsopp et al., 2003 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    With increased age, the absolute number of muscle stem cells declines, compounding the proliferative defect and leading to an even greater deficit in cells available for muscle repair.

    “With increased age the absolute number of MuSC declines (Fig. 4C), compounding the proliferative defect leading to an even more pronounced deficit in cells available for muscle repair.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Muscles from DMD patients have shorter telomeres than healthy individuals.

    “Muscles from DMD patients have been reported to have shorter telomeres than healthy individuals (Decary et al., 2000; Mouly et al., 2005).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Decary et al., 2000 source

      Not checked in the free run.

    • cites Mouly et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The breeding strategy produced same-strain dystrophic mice lacking telomerase, which is critical because telomere length differs among mouse strains.

    “This strategy yields same strain dystrophic mice that lack telomerase, which is critical, as telomere length differs among mouse strains (Hemann et al., 2001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hemann et al., 2001 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All animal protocols were approved by the Stanford University Administrative Panel on Laboratory Animal Care.

    “All protocols were approved by the Stanford University Administrative Panel on Laboratory Animal Care.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    A persistent need for MuSC proliferation in vivo leads to telomere shortening, senescence-like behavior, and tissue degeneration.

    “indicating that a persistent need for MuSC proliferation in vivo leads to telomere shortening, consequent senescence-like behavior, and tissue degeneration.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: A major difference between humans and mice is telomere length, which is substantially shorter in humans.
    • Rests on an assumption: Even in the setting of continuous damage, the mdx model shows only a mild muscle phenotype and no evidence for telomere shortening in myoblasts.

  • May combine two claims.

    Study design and conductown data

    Lentiviral GFP infection efficiency in freshly isolated MuSC was approximately 95% and comparable among groups.

    “The infection efficiency approximated 95% and was comparable among groups (P>0.05; data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    mdx/mTRG2 mice can mount an inflammatory response to tissue injury, and their hematopoietic compartment is not compromised.

    “These results indicate that mdx/mTRG2 mice are competent to mount an inflammatory response to tissue injury and provide direct evidence that the hematopoietic compartment is not compromised.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The severe phenotype in mdx/mTRG2 mice is muscle-specific and not caused by functional defects in other cell types.

    “suggesting that the severe phenotype is muscle-specific and is not the result of functional defects in other cell types.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Infection efficiency was approximately 90% and did not differ statistically among samples (P>0.05).

    “The infection efficiency approximated 90%, and was not statistically different among samples (Fig. 7B, P>0.05).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Satellite cell differentiation properties do not differ between mdx/mTRHet and mdx/mTRG2 cells, whereas proliferative function does.

    “These data confirm that satellite cell differentiation properties do not differ, whereas the proliferative function does.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    Studies were restricted to male mice because the disease is X-linked and sex differences can confound results.

    “Finally, our studies were restricted to male mice, as the disease is X-linked and differences in sex can confound results.”
    Quote in the paperSubstantial claim
62 of 62

  • The paper relies on this without support.

    The reason for the difference in severity between mice and humans with dystrophin deficiency is unknown.

    “To date, the basis for the observed mild effects in mice and lethal effects in humans of the same genetic absence of dystrophin remain unknown.”

  • The paper relies on this without support.

    The pathophysiological cause of the failure of muscle repair in DMD patients is not understood.

    “the pathophysiological cause of the failure of the repair process in muscles of DMD patients is not understood.”

  • The paper relies on this without support.

    No animal model closely recapitulates DMD progression in humans.

    “A major challenge hindering the development of effective therapies for DMD has been the lack of an animal model that closely recapitulates the disease progression in humans.”

  • The paper relies on this without support.

    In DMD, repeated myofiber damage creates a continuous demand for regeneration, and muscle tissue is eventually replaced by fibrosis, calcium deposits, and adipose tissue.

    “In DMD, unrelenting, recurrent myofiber damage elicits a constant need for regeneration. Eventually, muscle tissue is supplanted by fibrosis, calcium deposits and adipose accumulation that coincides with clinical manifestations.”

  • The paper relies on this without support.

    The absence of a mouse model for DMD that faithfully mimics key features of the human disease has limited understanding of its pathophysiology and tests of potential therapies.

    “The absence of a mouse model for DMD that faithfully mimics key features of the human disease has limited our understanding of its pathophysiology and tests of potential therapies.”

  • The paper relies on this without support.

    A longstanding enigma is why humans with a dystrophin mutation suffer from severe muscle wasting whereas mice with the same mutation do not.

    “A longstanding enigma has been why humans with a dystrophin mutation suffer from such severe muscle wasting, whereas mice with the same mutation do not.”

  • The paper relies on this without support.

    A major difference between humans and mice is telomere length, which is substantially shorter in humans.

    “A major difference between humans and mice is the length of their telomeres, which are substantially shorter in humans.”

  • The paper relies on this without support.

    The etiology of fibrosis in DMD remains unknown.

    “The etiology of the fibrosis observed in DMD remains unknown.”

  • The paper relies on this without support.

    Skeletal muscle is a stable tissue, and a muscle phenotype in mice lacking TERT and Terc has never been reported.

    “By contrast, skeletal muscle is a stable tissue, and a muscle phenotype in mice lacking TERT and Terc has never been reported.”

  • The paper relies on this without support.

    Even in the setting of continuous damage, the mdx model shows only a mild muscle phenotype and no evidence for telomere shortening in myoblasts.

    “Even in the setting of continuous damage, the mdx model, only a mild muscle phenotype is apparent and there is no evidence for telomere shortening in myoblasts of these mice.”
10 of 10

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In DMD, repeated injury creates a constant need for regeneration, which reduces muscle stem cell regenerative capacity through replicative aging.

    “Repetitive damage, caused by continual degeneration of structurally unsound DMD fibers, elicits constant demand for regeneration, diminishing the regenerative capacity of muscle stem cells as a consequence of replicative aging134.”

    From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [134]

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. McDonald CM Abresch RT Carter GT Fowler WM Jr Johnson ER Kilmer DD Sigford BJ 1995 Profiles of neuromuscular diseases. Duchenne muscular dystrophy Am J Phys Med Rehabil 74 S70 92 7576424
  2. Webster C Filippi G Rinaldi A Mastropaolo C Tondi M Siniscalco M Blau HM 1986 The myoblast defect identified in Duchenne muscular dystrophy is not a primary expression of the DMD mutation. Clonal analysis of myoblasts from five double heterozygotes for two X-linked loci: DMD and G6PD Hum Genet 74 74 80 3463532

Cited by

Sorted by citations

Authors
Sacco, A., Mourkioti, F., Tran, R., Choi, J., Llewellyn, M., Kraft, P., Shkreli, M., Delp, S., Pomerantz, J. H., Artandi, S. E., & Blau, H. M.
Affiliations
  • Institute for Stem Cell Biology and Regenerative Medicine (US)
  • Stanford Medicine (US)
  • Stanford University (US)
Corresponding author
  • Pomerantz, Jason H.
  • Blau, Helen M.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2010-12
Volume
143
Issue
7
Pages
1059-1071
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2010.11.039
PMC
PMC3025608
OpenAlex
W2157735441
Semantic Scholar
3be2e8b890722901df261591b11c1b974ac9c38b
Cited by
512
References
56
Citations by year
2026: 19 · 2025: 11 · 2024: 29 · 2023: 32 · 2022: 33 · 2021: 36 · 2020: 38 · 2019: 32 · 2018: 46 · 2017: 26 · 2016: 24 · 2015: 48 · 2014: 41 · 2013: 29 · 2012: 43
FWCI
12.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (AG-020961, AG009521, R37AG009521, R01AG009521, R01AG020961)
  • National Heart, Lung, and Blood Institute (U01HL100397, R01HL096113)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
Duchenne muscular dystrophy, mdx mice, telomere shortening, telomerase RNA, muscle stem cells, dystrophin deficiency, muscle regeneration, muscle atrophy, stem cell transplantation, disease progression, skeletal muscle degeneration
MeSH terms
Animals, Disease Models, Animal, Humans, Muscular Dystrophy, Animal, Prejudice, Stem Cells, Dystrophin, Telomere, Mice, Inbred mdx, Muscular Dystrophy, Duchenne, Cell Proliferation, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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