The Ubiquitin-Proteasome System Is Indispensable for the Maintenance of Muscle Stem Cells

Summary Adult muscle stem cells (satellite cells) are required for adult skeletal muscle regeneration. A proper balance between quiescence, proliferation, and differentiation is essential for the maintenance of the satellite cell pool and their regenerative function. Although the ubiquitin-proteasome is required for most protein degradation in mammalian cells, how its dysfunction affects tissue stem cells remains unclear. Here, we investigated the function of the proteasome in satellite cells using mice lacking the crucial proteasomal component, Rpt3. Ablation of Rpt3 in satellite cells decreased proteasome activity. Proteasome dysfunction in Rpt3-deficient satellite cells impaired their ability to proliferate, survive and differentiate, resulting in defective muscle regeneration. We found that inactivation of proteasomal activity induced proliferation defects and apoptosis in satellite cells. Mechanistically, insufficient proteasomal activity upregulated the p53 pathway, which caused cell-cycle arrest. Our findings delineate a critical function of the proteasome system in maintaining satellite cells in adult muscle.

• Publication year

  2018

• Venue

  Stem Cell Reports

• Publication date

  2018-11-08

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.stemcr.2018.10.009PMID 30416048PMCID 6294073
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Visualization of PAX7 protein dynamics in muscle satellite cells in a YFP knock-in-mouse line

  2018cited by this paper
• The Satellite Cell Niche Regulates the Balance between Myoblast Differentiation and Self-Renewal via p53

  2018cited by this paper
• The Logic of the 26S Proteasome.

  2017cited by this paper
• Emerging new tools to study and treat muscle pathologies: genetics and molecular mechanisms underlying skeletal muscle development, regeneration, and disease

  2017cited by this paper
• Visualizing the Functional Heterogeneity of Muscle Stem Cells.

  2016cited by this paper
• The central role of muscle stem cells in regenerative failure with aging

  2015cited by this paper
• Muscle stem cell fate is controlled by the cell-polarity protein Scrib.

  2015cited by this paper
• Proteasome dysfunction induces muscle growth defects and protein aggregation

  2014influential reference
• Proteostasis and aging of stem cells.

  2014cited by this paper
• Pax7 is critical for the normal function of satellite cells in adult skeletal muscle

  2013cited by this paper
• Satellite cells and the muscle stem cell niche.

  2013influential reference
• Failure of Amino Acid Homeostasis Causes Cell Death following Proteasome Inhibition

  2012cited by this paper
• Proteasome inhibition upregulates Bim and induces caspase-3-dependent apoptosis in human mast cells expressing the Kit D816V mutation

  2012cited by this paper
• Motor Neuron-specific Disruption of Proteasomes, but Not Autophagy, Replicates Amyotrophic Lateral Sclerosis*

  2012cited by this paper
• RPN-6 determines C. elegans longevity under proteotoxic stress conditions

  2012cited by this paper
• Satellite cells are essential for skeletal muscle regeneration: the cell on the edge returns centre stage

  2012cited by this paper
• Decreased proteasomal activity causes age-related phenotypes and promotes the development of metabolic abnormalities.

  2012cited by this paper
• Proteasome inhibitors induce p53-independent apoptosis in human cancer cells.

  2011cited by this paper
• Pax 7-expressing satellite cells are indispensable for adult skeletal muscle regeneration

  2011cited by this paper
• Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration

  2011cited by this paper
• Transcriptional mechanisms regulating skeletal muscle differentiation, growth and homeostasis

  2011cited by this paper
• An absolute requirement for Pax7-positive satellite cells in acute injury-induced skeletal muscle regeneration

  2011cited by this paper
• Identification and characterization of a non-satellite cell muscle resident progenitor during postnatal development

  2010cited by this paper
• Inducible lineage tracing of Pax7‐descendant cells reveals embryonic origin of adult satellite cells

  2010cited by this paper
• Targeting proteins for degradation.

  2009cited by this paper
• Blinded by the Light: The Growing Complexity of p53.

  2009influential reference
• Comparison of rat liver and brain proteasomes for oxidative stress-induced inactivation: Influence of ageing and dietary restriction

  2009cited by this paper
• Genetic Evidence Linking Age-Dependent Attenuation of the 26S Proteasome with the Aging Process

  2008cited by this paper
• A coordinated action of Bax, PUMA, and p53 promotes MG132-induced mitochondria activation and apoptosis in colon cancer cells

  2007cited by this paper
• The proteasomal subunit S6 ATPase is a novel synphilin‐1 interacting protein—implications for Parkinson's disease

  2007cited by this paper
• Apoptosis induced by proteasome inhibition in cancer cells: predominant role of the p53/PUMA pathway

  2007cited by this paper
• Ump1 extends yeast lifespan and enhances viability during oxidative stress: central role for the proteasome?

  2006cited by this paper
• Altered proteasome structure, function, and oxidation in aged muscle

  2005cited by this paper
• Cellular and molecular signatures of muscle regeneration: current concepts and controversies in adult myogenesis.

  2005cited by this paper
• Protein Synthesis upon Acute Nutrient Restriction Relies on Proteasome Function

  2005cited by this paper
• Proteasomal activity in brain differs between species and brain regions and changes with age.

  2005cited by this paper
• Cellular and molecular regulation of muscle regeneration.

  2004cited by this paper
• Muscle satellite cells.

  2003cited by this paper
• Cell Therapy of α-Sarcoglycan Null Dystrophic Mice Through Intra-Arterial Delivery of Mesoangioblasts

  2003cited by this paper
• Myogenic and nonmyogenic cells differentially express proteinases, Hsc/Hsp70, and BAG-1 during skeletal muscle regeneration.

  2003cited by this paper
• Looking back to the embryo: defining transcriptional networks in adult myogenesis

  2003cited by this paper
• Protein degradation and protection against misfolded or damaged proteins

  2003cited by this paper
• Molecular regulation of muscle cachexia: it may be more than the proteasome.

  2002cited by this paper
• Age-dependent declines in proteasome activity in the heart.

  2002cited by this paper
• P53 Regulates Myogenesis by Triggering the Differentiation Activity of Prb

  2000cited by this paper
• Mouse proteasomal ATPases Psmc3 and Psmc4: genomic organization and gene targeting.

  2000cited by this paper
• Reduced Differentiation Potential of Primary MyoD−/− Myogenic Cells Derived from Adult Skeletal Muscle

  1999cited by this paper
• The Proteasome : Paradigm Review of a Self-Compartmentalizing Protease and unfolding

  1998cited by this paper
• The proteasome: paradigm of a self-compartmentalizing protease.

  1998cited by this paper
• p53 protein is activated during muscle differentiation and participates with MyoD in the transcription of muscle creatine kinase gene

  1998cited by this paper
• Ubiquitin-proteasome-dependent proteolysis in skeletal muscle.

  1998cited by this paper
• Inhibitors of the proteasome block the myogenic differentiation of rat L6 myoblasts

  1998cited by this paper
• Degradation of Myogenic Transcription Factor MyoD by the Ubiquitin Pathway In Vivo and In Vitro: Regulation by Specific DNA Binding

  1998cited by this paper
• Age-related changes in the 20S and 26S proteasome activities in the liver of male F344 rats.

  1998cited by this paper
• Proteasome and myogenesis

  1997cited by this paper
• Interference with p53 protein inhibits hematopoietic and muscle differentiation

  1996cited by this paper
• In vivo ubiquitination and proteasome-mediated degradation of p53(1).

  1996cited by this paper
• Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD

  1995cited by this paper
• The MCK enhancer contains a p53 responsive element.

  1991cited by this paper
• SATELLITE CELL OF SKELETAL MUSCLE FIBERS

  1961cited by this paper
• An absolute requirement for Pax 7-positive satellite cells in acute injury-induced skeletal muscle regeneration

  year unknowncited by this paper

• Organ-Specific Regulation of Systemic Aging: Focus on the Brain, Skeletal Muscle, and Gut

  2026cites this paper
• Fucoidan attenuates age-related skeletal muscle atrophy via gut microbiota-dependent tryptophan metabolic Remodeling.

  2026cites this paper
• Carnosic acid attenuates ventilator-induced diaphragmatic dysfunction via activation of the Nrf2/HO-1 pathway.

  2025cites this paper
• Inhibition of methionine aminopeptidase in C2C12 myoblasts disrupts cell integrity via increasing endoplasmic reticulum stress.

  2025cites this paper
• Harnessing the ubiquitin proteasome system as a key player in stem cell biology

  2025cites this paper
• Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age

  2025cites this paper
• Loss of Tob1 promotes muscle regeneration through muscle stem cell expansion.

  2024cites this paper
• The E3 ubiquitin ligase Nedd4L preserves skeletal muscle stem cell quiescence by inhibiting their activation

  2024cites this paper
• Regulation of adult stem cell quiescence and its functions in the maintenance of tissue integrity

  2023cites this paper
• PAC1 Deficiency Protects Obese Male Mice From Immobilization-Induced Muscle Atrophy by Suppressing FoxO–Atrogene Axis

  2023cites this paper
• NEDD4-1 deficiency impairs satellite cell function during skeletal muscle regeneration

  2023cites this paper
• The E3 Ubiquitin Ligase Nedd4L Acts as a Checkpoint Against Activation in Quiescent Muscle Stem Cells

  2023cites this paper
• The aminopeptidase LAP3 suppression accelerates myogenic differentiation via the AKT‐TFE3 pathway in C2C12 myoblasts

  2023cites this paper
• Degradative Signaling in ATG7-Deficient Skeletal Muscle Following Cardiotoxin Injury

  2023cites this paper
• Understanding neurodevelopmental proteasomopathies as new rare disease entities: A review of current concepts, molecular biomarkers, and perspectives

  2023cites this paper
• Research progress on the pathogenesis and treatment of ventilator-induced diaphragm dysfunction

  2023cites this paper
• The Role of Ubiquitin–Proteasome System in the Biology of Stem Cells

  2023cites this paper
• Role of ubiquitin-proteasome system in stem cell biology

  2023cites this paper
• The Proteasome and Ageing.

  2023cites this paper
• The Gentle Side of the UPS: Ubiquitin-Proteasome System and the Regulation of the Myogenic Program

  2022cites this paper
• Importance of clitellar tissue in the regeneration ability of earthworm Eudrilus eugeniae

  2022cites this paper
• Balenine, Imidazole Dipeptide Promotes Skeletal Muscle Regeneration by Regulating Phagocytosis Properties of Immune Cells

  2022cites this paper
• Contribution of muscle satellite cells to sarcopenia

  2022cites this paper
• Three‐dimensional chromatin re‐organization during muscle stem cell aging

  2022cites this paper
• Little involvement of recycled-amino acids from proteasomal proteolysis in de novo protein synthesis.

  2022cites this paper
• Decline of regenerative potential of old muscle stem cells: contribution to muscle aging

  2022cites this paper
• A Long Journey before Cycling: Regulation of Quiescence Exit in Adult Muscle Satellite Cells

  2022cites this paper
• Extensive remodeling of the extracellular matrix during aging contributes to age-dependent impairments of muscle stem cell functionality.

  2021cites this paper
• Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation

  2021cites this paper
• RFWD3 Participates in the Occurrence and Development of Colorectal Cancer via E2F1 Transcriptional Regulation of BIRC5

  2021cites this paper
• Control of satellite cell function in muscle regeneration and its disruption in ageing

  2021cites this paper
• A Bioassay-Guided Fractionation of Rosemary Leaf Extract Identifies Carnosol as a Major Hypertrophy Inducer in Human Skeletal Muscle Cells

  2021cites this paper
• Ubiquitin-specific peptidase 8 regulates proliferation and early differentiation of sheep skeletal muscle satellite cells

  2021cites this paper
• Perspectives on skeletal muscle stem cells

  2021cites this paper
• Reprogrammed Stem Cells and Ageing Suppression Hemshankar International Journal of Stem Cells & Research

  2020cites this paper
• (1 → 3)-β-d-glucan enhances the toxicity induced by Bortezomib in rat testis.

  2020cites this paper
• The impact of intracellular aminopeptidase on C2C12 myoblast proliferation and differentiation.

  2020cites this paper
• Post-Transcriptional Regulation of Homeostatic, Stressed, and Malignant Stem Cells.

  2020cites this paper
• A Cdh1–FoxM1–Apc axis controls muscle development and regeneration

  2020cites this paper
• Stem Cell Aging in Skeletal Muscle Regeneration and Disease

  2020cites this paper
• Satellite cells in ageing: use it or lose it

  2020cites this paper
• Preclinical Molecular Signatures of Spinal Cord Functional Restoration: Optimizing the Metamorphic Axolotl (Ambystoma mexicanum) Model in Regenerative Medicine

  2020cites this paper
• Stem Cell Aging: The Upcoming Era of Proteins and Metabolites.

  2020cites this paper
• A Modified Pre-plating Method for High-Yield and High-Purity Muscle Stem Cell Isolation From Human/Mouse Skeletal Muscle Tissues

  2020cites this paper
• Inducible Rpt3, a Proteasome Component, Knockout in Adult Skeletal Muscle Results in Muscle Atrophy

  2020cites this paper
• Autophagy under glucose starvation enhances protein translation initiation in response to re‐addition of glucose in C2C12 myotubes

  2020cites this paper
• Down-regulation of RFWD3 inhibits cancer cells proliferation and migration in gastric carcinoma.

  2020influential citation
• The ubiquitin–proteasome system in regulation of the skeletal muscle homeostasis and atrophy: from basic science to disorders

  2020cites this paper
• Transcriptomic analysis of early stages of intestinal regeneration in Holothuria glaberrima

  2020cites this paper
• siRNA knockdown of alanine aminopeptidase impairs myoblast proliferation and differentiation.

  2020cites this paper
• Dietary Antioxidant Supplementation Promotes Growth in Senegalese Sole Postlarvae

  2020cites this paper
• Protein quality control of cell stemness

  2020cites this paper
• Stem cell quiescence and its clinical relevance

  2020cites this paper
• Puromycin‐sensitive aminopeptidase is required for C2C12 myoblast proliferation and differentiation

  2020cites this paper
• Apoptosomes and proteasomes from exosomes generated by human hematopoietic stem cells

  2020cites this paper
• HUMAN HEMATOPOIETIC STEM CELLS GENERATE EXOSOMES CONTAINING ACTIVE PROTEASOMES BUT NOT CASPASES

  2020cites this paper
• Structure of proteins: Evolution with unsolved mysteries.

  2019cites this paper
• Muscle Injury Associated Elevated Oxidative Stress and Abnormal Myogenesis in Patients with Idiopathic Scoliosis

  2019cites this paper
• Proteasome dysfunction in alveolar type 2 epithelial cells is associated with acute respiratory distress syndrome

  2019cites this paper
• Walk the Line: The Role of Ubiquitin in Regulating Transcription in Myocytes.

  2019influential citation