Orienting Muscle Stem Cells for Regeneration in Homeostasis, Aging, and Disease

Feige, Peter; Brun, Caroline E.; Ritso, Morten; Rudnicki, Michael A.

doi:10.1016/j.stem.2018.10.006

Cited by 191 publications

(183 citation statements)

References 102 publications

(159 reference statements)

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“…In aged mice, skeletal muscle function and regenerative capacity are lost arising from cell intrinsic and environmental changes that occur during aging (Blau et al, 2015;Feige et al, 2018;Hwang & Brack, 2018;Sousa-Victor et al, 2015). We queried the skeletal muscle environment in geriatric mice (30 mo old) to determine the extent of transcriptional changes in the cell cohorts we identified in uninjured and injured adult mouse skeletal muscle (3 mo old).…”

Section: Supplemental Information Fig S4 and Supplemental Informationmentioning

confidence: 99%

“…Muscle regeneration is impaired with age, and alterations to extrinsic factors contribute to agedinduced deficiencies. (Blau, Cosgrove, & Ho, 2015;Feige, Brun, Ritso, & Rudnicki, 2018;Hwang & Brack, 2018;Sousa-Victor, García-Prat, Serrano, Perdiguero, & Muñoz-Cánoves, 2015). Given the multitude of cells and extrinsic factors required for skeletal muscle function, generating a cellular inventory and single cell transcriptional profile for muscle regeneration and aging muscle will permit correlation of dynamic changes in cell populations that may influence each other to effectively and rapidly regenerate muscle tissue.…”

Section: Introductionmentioning

confidence: 99%

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The regenerating skeletal muscle niche guides muscle stem cell self-renewal

Cutler

Pawlikowski²,

Wheeler

et al. 2019

Preprint

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An individual skeletal muscle is a complex structure, composed of large contractile myofibers, connective tissue, nerve tissue, immune cells, stem cells and the vasculature. Each of these components contribute to skeletal muscle function, maintenance, regeneration, and if perturbed can potentially contribute to or cause disease that reduces muscle function. To investigate the cellular inventory of skeletal muscle we carried out single cell RNA sequencing on cells isolated from adult uninjured muscle, adult post injury muscle, and from aged uninjured muscle. Our muscle atlas provides the cellular landscape and partial transcriptome of pre-injury, post injury, and aged muscle, identifying dramatic changes in the muscle stem cell, fibroblast and immune cell populations during regeneration. Our data highlight dynamic changes occurring during muscle regeneration, identify potential extrinsic mechanisms that control muscle stem cell behavior, and underscore the inflamed state of aged uninjured muscle.

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Section: Supplemental Information Fig S4 and Supplemental Informationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The regenerating skeletal muscle niche guides muscle stem cell self-renewal

Cutler

Pawlikowski²,

Wheeler

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…In mammalian muscle tissue, aging results in a decrease in muscle mass and regenerative potential. Loss of regenerative function has been attributed both to cell-intrinsic changes in muscle stem cells (MuSCs) and cell-extrinsic changes in the tissue environment [16,12,25]. Additional evidence suggests that age-related changes in fibro/adipose progenitors (FAPs), a mesenchymal progenitor population, may also play a role [12,50].…”

Section: Introductionmentioning

confidence: 99%

Differentiation reveals the plasticity of age-related change in murine muscle progenitors

Kimmel

Hendrickson

Kelley

2020

Preprint

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Skeletal muscle experiences a decline in lean mass and regenerative potential with age, in part due to intrinsic changes in progenitor cells. However, it remains unclear if age-related changes in progenitors persist across a differentiation trajectory or if new age-related changes manifest in differentiated cells. To investigate this possibility, we performed single cell RNA-seq on muscle mononuclear cells from young and aged mice and profiled muscle stem cells (MuSCs) and fibro/adipose progenitors (FAPs) after differentiation. Differentiation increased the magnitude of age-related change in MuSCs and FAPs, but also masked a subset of age-related changes present in progenitors. Using a dynamical systems approach and RNA velocity, we found that aged MuSCs follow the same differentiation trajectory as young cells, but stall in differentiation near a commitment decision. Our results suggest that age-related changes are plastic across differentiation trajectories and that fate commitment decisions are delayed in aged myogenic cells.

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“…4). Selfrenewal and return to quiescence are pivotal toward maintenance of the satellite cell pool (reviewed in Feige et al, 2018;Forcina et al, 2019), and may explain why endurance exercise promotes more favorable repair after injury.…”

Section: Discussionmentioning

confidence: 99%

Adult Muscle Stem Cell Self-Renewal Induced by Endurance Exercise is Mediated by Inhibition of Mitochondrial Oxygen Consumption

Abreu

Kowaltowski

2019

Preprint

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Skeletal muscle stem cells (satellite cells) are well known to participate in regeneration and maintenance of the tissue over time. Studies have shown increases in the number of satellite cells after exercise, but their functional role in endurance training remains unexplored. Here, we found that injured muscles from endurance-exercised mice display improved regenerative capacity, demonstrated through higher densities of newly formed myofibers compared to controls, as well as lower inflammation and fibrosis. Enhanced myogenic function was accompanied by an increased fraction of satellite cells expressing self-renewal markers. Control satellite cells had morphologies suggestive of early differentiation, while endurance exercise enhanced myogenic colony formation. The beneficial effects of endurance exercise were associated with satellite cell metabolic reprogramming, including reduced mitochondrial respiration (O 2 consumption) under resting conditions (absence of muscle injury) and increased stemness. During proliferation or activated states (three days after injury), O 2 consumption was equal in control and exercised cells. Surprisingly, inhibition of mitochondrial O 2 consumption was sufficient to enhance muscle stem cell self-renewal characteristics in vitro. Moreover, transplanted muscle satellite cells from exercised mice or cells with reduced mitochondrial respiration promoted a significant reductionin inflammation compared to controls. We propose that endurance exercise promotes self-renewal and inhibits differentiation in satellite cells, an effect promoted by metabolic reprogramming and respiratory inhibition, and which is associated with a more favorable muscular response to injury.

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Orienting Muscle Stem Cells for Regeneration in Homeostasis, Aging, and Disease

Cited by 191 publications

References 102 publications

The regenerating skeletal muscle niche guides muscle stem cell self-renewal

The regenerating skeletal muscle niche guides muscle stem cell self-renewal

Differentiation reveals the plasticity of age-related change in murine muscle progenitors

Adult Muscle Stem Cell Self-Renewal Induced by Endurance Exercise is Mediated by Inhibition of Mitochondrial Oxygen Consumption

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