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*

*Autor correspondiente de este trabajo

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

5 Citas (Scopus)

Resumen

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.

Idioma originalInglés
Páginas (desde-hasta)489-505.e7
PublicaciónDevelopmental Cell
Volumen58
N.º6
DOI
EstadoPublicada - 2023

Nota bibliográfica

Funding Information:
This work was supported by grants from the NIH (T32 AG000266 and K99 AG053438) to M.N.W. and by grants from the Glenn Foundation for Aging Research, the NIH (P01 AG036695, R01 AG052962, and R01AG055755), and the Department of Veterans Affairs (BLR&D Merit Review) to T.A.R. E.J. is supported by an OSAP Ontario Graduate Scholarship and a Cecil Yip Doctoral Award from the Donnelly Centre for Cellular and Biomolecular Research. P.M.G. is the Canada Research Chair in Endogenous Repair and receives support for this study from Medicine by Design, a Canada First Research Excellence Program, and the Canadian Institutes of Health Research. H.L. is supported by Ontario Graduate Scholarship. L.W.T. is funded by the Four-Year Doctoral Fellowship (4YF) from the University of British Columbia and the Dennis Washington Leadership Graduate Scholarship from the Dennis and Phyllis Washington Foundation. D.Z. and J.P.H. are supported by Chilean National Fund for Scientific and Technological Development FONDECYT 1170614. M.N.W. is supported by K99/R00 AG053438. We would like to thank Dr. Morten Ritso, UBC, for critical reading of the manuscript. We also thank Tiffany Huang, UBC, for helping with some experiments and quantifications. Graphical abstract created using Biorender.com. N.K. designed, directed, and carried out experiments, analyzed data, analyzed and interpreted data, prepared figures, and wrote the manuscript. M.L. E.J. and H.L. performed research, analyzed data, interpreted data, and prepared figures. L.W.T. analyzed data, interpreted data, and prepared figures. F.B. D.G. D.Z. C.K.W. and M.N.W. carried out experiments and analyzed data. T.A.R. J.P.H. W.T.G. and P.M.G. directed the research, interpreted data, and reviewed the manuscript. F.M.V.R. supervised the project, directed the project, and edited the manuscript. The authors declare no competing interests.

Funding Information:
This work was supported by grants from the NIH ( T32 AG000266 and K99 AG053438 ) to M.N.W. and by grants from the Glenn Foundation for Aging Research , the NIH ( P01 AG036695 , R01 AG052962 , and R01AG055755 ), and the Department of Veterans Affairs (BLR&D Merit Review) to T.A.R. E.J. is supported by an OSAP Ontario Graduate Scholarship and a Cecil Yip Doctoral Award from the Donnelly Centre for Cellular and Biomolecular Research. P.M.G. is the Canada Research Chair in Endogenous Repair and receives support for this study from Medicine by Design, a Canada First Research Excellence Program, and the Canadian Institutes of Health Research. H.L. is supported by Ontario Graduate Scholarship . L.W.T. is funded by the Four-Year Doctoral Fellowship (4YF) from the University of British Columbia and the Dennis Washington Leadership Graduate Scholarship from the Dennis and Phyllis Washington Foundation. D.Z. and J.P.H. are supported by Chilean National Fund for Scientific and Technological Development FONDECYT 1170614 . M.N.W. is supported by K99/R00 AG053438 . We would like to thank Dr. Morten Ritso, UBC, for critical reading of the manuscript. We also thank Tiffany Huang, UBC, for helping with some experiments and quantifications. Graphical abstract created using Biorender.com .

Publisher Copyright:
© 2023 Elsevier Inc.

Áreas temáticas de ASJC Scopus

  • Biología molecular
  • Bioquímica, Genética y Biología Molecular General
  • Biología del desarrollo
  • Biología celular

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