Activation of β-catenin in mesenchymal progenitors leads to muscle mass loss

Nasim Kajabadi; Marcela Low; Erik Jacques; Heta Lad; Lin Wei Tung; Farshad Babaeijandaghi; Daniel Gamu; Diego Zelada; Chi Kin Wong; Chihkai Chang; Lin Yi; Michael N Wosczyna; Thomas A Rando; Juan Pablo Henríquez; William T Gibson; Penney M Gilbert; Fabio M V Rossi

doi:10.1016/j.devcel.2023.02.009

Activation of β-catenin in mesenchymal progenitors leads to muscle mass loss

Dev Cell. 2023 Mar 27;58(6):489-505.e7. doi: 10.1016/j.devcel.2023.02.009. Epub 2023 Mar 9.

Authors

Nasim Kajabadi¹, Marcela Low², Erik Jacques³, Heta Lad³, Lin Wei Tung¹, Farshad Babaeijandaghi¹, Daniel Gamu⁴, Diego Zelada⁵, Chi Kin Wong⁴, Chihkai Chang¹, Lin Yi¹, Michael N Wosczyna⁶, Thomas A Rando⁷, Juan Pablo Henríquez⁵, William T Gibson⁴, Penney M Gilbert⁸, Fabio M V Rossi⁹

Affiliations

¹ School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
² School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada; Carrera de Química y Farmacia, Facultad de Medicina y Ciencia, Universidad San Sebastián, General Lagos 1163, 5090000 Valdivia, Chile.
³ Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
⁴ BC Children's Hospital Research Institute, 938 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Department of Medical Genetics, University of British Columbia, C201, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
⁵ Neuromuscular Studies Laboratory (NeSt Lab), GDeP, Department of Cell Biology, Universidad de Concepción, Concepción, Chile.
⁶ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Musculoskeletal Research Center, Bioengineering Institute, Department of Orthopedic Surgery, NYU Grossman School of Medicine, New York, NY 10010, USA; Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Tissue Regeneration, Repair and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
⁷ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Tissue Regeneration, Repair and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
⁸ Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
⁹ School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada. Electronic address: fabio@brc.ubc.ca.

PMID: 36898377
DOI: 10.1016/j.devcel.2023.02.009

Abstract

Loss of muscle mass is a common manifestation of chronic disease. We find the canonical Wnt pathway to be activated in mesenchymal progenitors (MPs) from cancer-induced cachectic mouse muscle. Next, we induce β-catenin transcriptional activity in murine MPs. As a result, we observe expansion of MPs in the absence of tissue damage, as well as rapid loss of muscle mass. Because MPs are present throughout the organism, we use spatially restricted CRE activation and show that the induction of tissue-resident MP activation is sufficient to induce muscle atrophy. We further identify increased expression of stromal NOGGIN and ACTIVIN-A as key drivers of atrophic processes in myofibers, and we verify their expression by MPs in cachectic muscle. Finally, we show that blocking ACTIVIN-A rescues the mass loss phenotype triggered by β-catenin activation in MPs, confirming its key functional role and strengthening the rationale for targeting this pathway in chronic disease.

Keywords: cancer-associated cachexia; canonical Wnt signaling; mesenchymal progenitors; muscle atrophy.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Activins
Animals
Mice
Muscles / metabolism
Wnt Signaling Pathway*
beta Catenin* / metabolism

Substances

beta Catenin
Activins

Abstract

Publication types

MeSH terms

Substances

Grants and funding