The endothelial Dll4–muscular Notch2 axis regulates skeletal muscle mass

Shin Fujimaki, Tomohiro Matsumoto, Masashi Muramatsu, Hiroshi Nagahisa, Naoki Horii, Daiki Seko, Shinya Masuda, Xuerui Wang, Yoko Asakura, Yukie Takahashi, Yuta Miyamoto, Shingo Usuki, Kei ichiro Yasunaga, Yasutomi Kamei, Ryuichi Nishinakamura, Takashi Minami, Takaichi Fukuda, Atsushi Asakura, Yusuke Ono

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Adult skeletal muscle is a highly plastic tissue that readily reduces or gains its mass in response to mechanical and metabolic stimulation; however, the upstream mechanisms that control muscle mass remain unclear. Notch signalling is highly conserved, and regulates many cellular events, including proliferation and differentiation of various types of tissue stem cell via cell–cell contact. Here we reveal that multinucleated myofibres express Notch2, which plays a crucial role in disuse- or diabetes-induced muscle atrophy. Mechanistically, in both atrophic conditions, the microvascular endothelium upregulates and releases the Notch ligand, Dll4, which then activates muscular Notch2 without direct cell–cell contact. Inhibition of the Dll4–Notch2 axis substantively prevents these muscle atrophy and promotes mechanical overloading-induced muscle hypertrophy in mice. Our results illuminate a tissue-specific function of the endothelium in controlling tissue plasticity and highlight the endothelial Dll4–muscular Notch2 axis as a central upstream mechanism that regulates catabolic signals from mechanical and metabolic stimulation, providing a therapeutic target for muscle-wasting diseases.

Original languageEnglish (US)
Pages (from-to)180-189
Number of pages10
JournalNature Metabolism
Volume4
Issue number2
DOIs
StatePublished - Feb 2022

Bibliographical note

Funding Information:
We thank R. Fujita, S. Ogawa, Y. Tsuchiya, K. Yoshioka, Y. Kitajima, D. T. Shima, Y. Kubota and N. Suzuki for sharing materials and technical assistance. We also thank S. Burden for providing Mlc1f-Cre mice; I. Imayoshi and R. Kageyama for providing Hes1-flox mice and T. Honjo for providing RBPJ-flox mice. The Pax7 and MF20 antibodies, developed by A. Kawakami and D.A. Fischman, respectively, were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa. This work was supported by the FOREST program of the Japan Science and Technology Agency (JST, grant no. JPMJFR205C to Y.O.), the Japan Agency for Medical Research and Development (AMED, grant no. JP19bm0704036 to Y.O.) and Grants-in-Aid for Scientific Research KAKENHI (grant nos. 25882024 to S.M.; 15H05368, 18H03193 and 20K21763 to Y.O.; 20K19641 to S.F. and 20J01669 to T.Ma.). This work was also supported, in part, by the Center for Metabolic Regulation of Healthy Aging (to Y.O. and S.F.), the Takeda Science Foundation (to Y.O. and S.F.), the Naito Foundation (to Y.O.), the Uehara Memorial Foundation (to S.F.), NIH R21 (grant no. AR078400 to A.A.) and Regenerative Medicine Minnesota (grant no. 092319 TR010 to A.A.). T.Ma., H.N. and N.H. were funded by a JSPS Research Fellowship.

Funding Information:
We thank R. Fujita, S. Ogawa, Y. Tsuchiya, K. Yoshioka, Y. Kitajima, D. T. Shima, Y. Kubota and N. Suzuki for sharing materials and technical assistance. We also thank S. Burden for providing Mlc1f-Cre mice; I. Imayoshi and R. Kageyama for providing Hes1-flox mice and T. Honjo for providing RBPJ-flox mice. The Pax7 and MF20 antibodies, developed by A. Kawakami and D.A. Fischman, respectively, were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa. This work was supported by the FOREST program of the Japan Science and Technology Agency (JST, grant no. JPMJFR205C to Y.O.), the Japan Agency for Medical Research and Development (AMED, grant no. JP19bm0704036 to Y.O.) and Grants-in-Aid for Scientific Research KAKENHI (grant nos. 25882024 to S.M.; 15H05368, 18H03193 and 20K21763 to Y.O.; 20K19641 to S.F. and 20J01669 to T.Ma.). This work was also supported, in part, by the Center for Metabolic Regulation of Healthy Aging (to Y.O. and S.F.), the Takeda Science Foundation (to Y.O. and S.F.), the Naito Foundation (to Y.O.), the Uehara Memorial Foundation (to S.F.), NIH R21 (grant no. AR078400 to A.A.) and Regenerative Medicine Minnesota (grant no. 092319 TR010 to A.A.). T.Ma., H.N. and N.H. were funded by a JSPS Research Fellowship.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

Fingerprint

Dive into the research topics of 'The endothelial Dll4–muscular Notch2 axis regulates skeletal muscle mass'. Together they form a unique fingerprint.

Cite this