Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging

Benjamin, D. M.; Brett, Jamie O.; Both, Pieter; Benjamin, Joel; Ishak, Heather L.; Kang, Jengmin; Kim, Soochi; Chung, Mingyu; Arjona, Marina; Nutter, Christopher W; Tan, Jenna H.; Krishnan, Ananya K.; Dulay, Hunter; Louie, Sharon M.; Morrée, Antoine de; Nomura, Daniel K.; Rando, Thomas A.

doi:10.1016/j.cmet.2023.02.001

Cited by 25 publications

(12 citation statements)

References 101 publications

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“…DNA damage and oxidative stress could also play a role in modulating muscle differentiation, since it has been shown that both DNA damage 60 and increased expression of HO-1 61 can inhibit C2C12 differentiation, the former by inhibiting muscle-specific genes 60 and the latter by targeting striated muscle specific miRNAs, called myomiRs 61 . Additionally, the decreased levels of reduced glutathione observed in our in vitro model ( Figure 1E ) are consistent with the previously described aged MuSCs 62 , which may explain the exhaustion of the pool of MuSCs previously observed in dy W fetuses 19 . Moreover, our data suggests Lama2 -deficiency triggers DNA damage, in both the in vitro model ( Figure 1J ) and in vivo in E17.5 fetuses ( Figures 5D and 7B ).…”

Section: Discussionsupporting

confidence: 92%

Deregulation of multiple mechanisms shapes the onset ofLAMA2-congenital muscular dystrophy

Martins,

Ribeiro,

Melo

et al. 2024

Preprint

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LAMA2-congenital muscular dystrophy (LAMA2-CMD) is the most common congenital muscular dystrophy. This often-lethal disease is triggered by mutations in LAMA2, coding for laminin-alpha2 chain, a key extracellular matrix (ECM) component, prevalent in the skeletal muscle. Several phenotypes have been associated with LAMA2-CMD, however, it is not yet known what mechanisms are faulty, right at disease onset in utero. Using the dyW mouse model of LAMA2-CMD we showed that the disease onset is characterized by a profound downregulation of gene expression, with a marked effect on cytoskeletal organization, myoblast differentiation and fusion and altered DNA repair and oxidative stress responses. Concordantly, we found that Lama2-deficient myoblast cells displayed proliferation and differentiation defects, increased oxidative stress and DNA damage. Together, our findings provide unique insights into the processes dependent on laminin-alpha2 chain during muscle development, revealing its critical importance to maintain muscle cell homeostasis already at fetal stages.

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Section: Discussionsupporting

confidence: 92%

Deregulation of multiple mechanisms shapes the onset ofLAMA2-congenital muscular dystrophy

Martins,

Ribeiro,

Melo

et al. 2024

Preprint

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“…for five days), which produces Nrf2-Gclc double-KO cells, as a control, since a lack of glutathione in these cells naturally increases ROS production and lipid peroxidation 49 . Notably, Glutathione Metabolism was also enriched in aged MuSCs ( Figure 6D ), consistent with altered glutathione metabolism, which is a hallmark of stem cell ageing 50 . Upon plating, the rate of lipid peroxidation dramatically increased (>4.5-fold increase) in aged MuSCs compared to that in younger cells, highlighting the enhanced sensitivity of aged MuSCs to oxidative and replicative stress outside their niche ( Figure 6K ).…”

Section: Resultssupporting

confidence: 60%

“…for ve days), which produces Nrf2-Gclc double-KO cells, as a control, since a lack of glutathione in these cells naturally increases ROS production and lipid peroxidation 49 . Notably, Glutathione Metabolism was also enriched in aged MuSCs (Figure 6D), consistent with altered glutathione metabolism, which is a hallmark of stem cell ageing 50 .…”

Section: Epigenetic Erosion Of H4k20 Drives Musc Population Drift Tow...supporting

confidence: 60%

Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis.

Blanc,

Shah,

Salama

et al. 2024

Preprint

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Aging is associated with a decline in stem cell functionality and number across the organism. In this study, we aimed to further unravel Muscle Stem Cells (MuSCs) aging by assessing how systemic factors influence MuSC fate decisions through long-term epigenetic landscape remodelling. As aging is intricately linked to a pro-inflammatory shift, we studied the epigenetic effects of inflammatory signals in MuSCs and measured decreased H4K20me1 levels. This loss disrupts MuSC quiescence, largely through epigenetic silencing of Notch target genes. In the setting of inflammatory signals or aging, the lack of Kmt5a and the subsequent absence of de novoH4K20me1 culminate in cell death by ferroptosis. Aged MuSCs manifest abnormal iron metabolism and reduced Gpx4 levels, resulting in the accumulation of intracellular iron, increased reactive oxygen species, genomic instability, and lipid peroxidation. We showed that ferroptosis is the predominant mode of cell death in aged MuSCs, with remarkably high levels of lipid peroxidation; a phenomenon we also observed in aged hematopoietic stem cells. Implementing preventative strategies to inhibit systemic inflammation prevented aged MuSC ferroptosis, preserving their numbers and regenerative capabilities. This intervention significantly enhanced aged muscle regeneration and strength recovery and extended both lifespan and healthspan in mice. This study delineates a previously underappreciated fate trajectory for stem cell aging, and offers meaningful insights into the treatment of age-related disorders.

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“…Notably, Glutathione Metabolism was also enriched in aged MuSCs (Fig. 6D), consistent with altered glutathione metabolism, which is a hallmark of stem cell ageing 50 . Upon plating, the rate of lipid peroxidation dramatically increased (> 4.5-fold increase) in aged MuSCs compared to that in younger cells, highlighting the enhanced sensitivity of aged MuSCs to oxidative and replicative stress outside their niche (Fig.…”

Section: Epigenetic Erosion Of H4k20 Drives Musc Population Drift Tow...supporting

confidence: 62%

Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis.

Blanc,

Shah,

Salama

et al. 2024

Preprint

View full text Add to dashboard Cite

Aging is associated with a decline in stem cell functionality and number across the organism. In this study, we aimed to further unravel Muscle Stem Cells (MuSCs) aging by assessing how systemic factors influence MuSC fate decisions through long-term epigenetic landscape remodelling. As aging is intricately linked to a pro-inflammatory shift, we studied the epigenetic effects of inflammatory signals in MuSCs and measured decreased H4K20me1 levels. This loss disrupts MuSC quiescence, largely through epigenetic silencing of Notch target genes. In the setting of inflammatory signals or aging, the lack of Kmt5a and the subsequent absence of de novo H4K20me1 culminate in cell death by ferroptosis. Aged MuSCs manifest abnormal iron metabolism and reduced Gpx4 levels, resulting in the accumulation of intracellular iron, increased reactive oxygen species, genomic instability, and lipid peroxidation. We showed that ferroptosis is the predominant mode of cell death in aged MuSCs, with remarkably high levels of lipid peroxidation; a phenomenon we also observed in aged hematopoietic stem cells. Implementing preventative strategies to inhibit systemic inflammation prevented aged MuSC ferroptosis, preserving their numbers and regenerative capabilities. This intervention significantly enhanced aged muscle regeneration and strength recovery and extended both lifespan and healthspan in mice. This study delineates a previously underappreciated fate trajectory for stem cell aging, and offers meaningful insights into the treatment of age-related disorders.

show abstract

Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging

Cited by 25 publications

References 101 publications

Deregulation of multiple mechanisms shapes the onset ofLAMA2-congenital muscular dystrophy

Deregulation of multiple mechanisms shapes the onset ofLAMA2-congenital muscular dystrophy

Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis.

Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis.

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