2. Academic Validation
  3. Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age

Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age

  • Nat Metab. 2025 Dec;7(12):2571-2588. doi: 10.1038/s42255-025-01411-w.
Ignacio Ramírez-Pardo 1 2 3,  Silvia Campanario 2 3,  Bhakti Chavda 4 5,  Olaya Santiago-Fernández 4 5,  Marta Flández 3 6 7,  Mercedes Grima-Terrén 1 2 3,  Andrés Cisneros 1 2,  Aina Calls-Cobos 2,  Daniel N Itzhak 8,  Bryan Ngo 8,  Sudha Janaki-Raman 8,  Edward D Kantz 8,  Laura Ortet 1,  Antonio Diaz 4 5,  Kristen Lindenau 4 5,  Julio Doménech-Fernández 9 10,  Mari Carmen Gómez-Cabrera 11,  Emilio Camafeita 12 13,  Jesús Vázquez 12 13,  Marta Martinez-Vicente 14,  Antonio L Serrano 1 2,  Eusebio Perdiguero 1 2,  Joan Isern 1 2 3,  Ana Maria Cuervo 15 16,  Pura Muñoz-Cánoves 17 18 19 20
Affiliations

Affiliations

  • 1 Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
  • 2 Altos Labs Inc., San Diego Institute of Science, San Diego, CA, USA.
  • 3 Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
  • 4 Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 5 Institute for Aging Research, Albert Einstein College of Medicine, New York City, NY, USA.
  • 6 Escuelab Innovación Educativa, Madrid, Spain.
  • 7 Faculty of Experimental Sciences, Francisco de Vitoria University (UFV), Pozuelo de Alarcón, Spain.
  • 8 Altos Labs, Bay Area Institute of Science, Redwood City, CA, USA.
  • 9 Servicio de Cirugía Ortopédica y Traumatología, Hospital Arnau de Vilanova, Valencia, Spain.
  • 10 Department of Orthopedic Surgery, Clinica Universidad de Navarra, Pamplona, Spain.
  • 11 Freshage Research Group, Department of Physiology, University of Valencia and CIBERFES. Fundación Investigación Hospital Clínico/INCLIVA, Valencia, Spain.
  • 12 Laboratory of Cardiovascular Proteomics, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
  • 13 CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
  • 14 Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR) Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain.
  • 15 Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA. ana-maria.cuervo@einsteinmed.edu.
  • 16 Institute for Aging Research, Albert Einstein College of Medicine, New York City, NY, USA. ana-maria.cuervo@einsteinmed.edu.
  • 17 Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra (UPF), Barcelona, Spain. pmunozcanoves@altoslabs.com.
  • 18 Altos Labs Inc., San Diego Institute of Science, San Diego, CA, USA. pmunozcanoves@altoslabs.com.
  • 19 Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. pmunozcanoves@altoslabs.com.
  • 20 ICREA, Barcelona, Spain. pmunozcanoves@altoslabs.com.
PMID: 41339968 DOI: 10.1038/s42255-025-01411-w
Abstract

Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated Autophagy (CMA) is a selective Autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration. Using comparative proteomics to identify CMA substrates, we find that actin Cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-112483
    99.48%, CMA激活剂
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