TY - JOUR
T1 - The endothelial Dll4–muscular Notch2 axis regulates skeletal muscle mass
AU - Fujimaki, Shin
AU - Matsumoto, Tomohiro
AU - Muramatsu, Masashi
AU - Nagahisa, Hiroshi
AU - Horii, Naoki
AU - Seko, Daiki
AU - Masuda, Shinya
AU - Wang, Xuerui
AU - Asakura, Yoko
AU - Takahashi, Yukie
AU - Miyamoto, Yuta
AU - Usuki, Shingo
AU - Yasunaga, Kei ichiro
AU - Kamei, Yasutomi
AU - Nishinakamura, Ryuichi
AU - Minami, Takashi
AU - Fukuda, Takaichi
AU - Asakura, Atsushi
AU - Ono, Yusuke
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
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U2 - 10.1038/s42255-022-00533-9
DO - 10.1038/s42255-022-00533-9
M3 - Article
C2 - 35228746
AN - SCOPUS:85125585127
SN - 2522-5812
VL - 4
SP - 180
EP - 189
JO - Nature Metabolism
JF - Nature Metabolism
IS - 2
ER -