TY - JOUR
T1 - Mesenchymal Bmp3b expression maintains skeletal muscle integrity and decreases in age-related sarcopenia
AU - Uezumi, Akiyoshi
AU - Ikemoto-Uezumi, Madoka
AU - Zhou, Heying
AU - Kurosawa, Tamaki
AU - Yoshimoto, Yuki
AU - Nakatani, Masashi
AU - Hitachi, Keisuke
AU - Yamaguchi, Hisateru
AU - Wakatsuki, Shuji
AU - Araki, Toshiyuki
AU - Morita, Mitsuhiro
AU - Yamada, Harumoto
AU - Toyoda, Masashi
AU - Kanazawa, Nobuo
AU - Nakazawa, Tatsu
AU - Hino, Jun
AU - Fukada, So Ichiro
AU - Tsuchida, Kunihiro
N1 - Funding Information:
We thank Se-Jin Lee for providing the Bmp3b/Gdf10-KO mice, and Kenji Kangawa and Mikiya Miyazato for their helpful discussions. We thank Editage (www.editage.com) for English language editing. AU was funded by JSPS KAKENHI grant number JP19H04063, an AMED Practical Research Project for Rare/Intractable Diseases (number 17ek0109174h9903), an Intramural Research Grant for Neurological and Psychiatric Disorders of NCNP (number 28-6), the Japan Foundation for Aging And Health, The Naito Foundation, The General Insurance Association of Japan, Research Fund of Mitsukoshi Health and Welfare Foundation, Astellas Foundation for Research on Metabolic Disorders, Research Fund of Mitsui Sumitomo Insurance Welfare Foundation, and ONO Medical Research Foundation.
PY - 2021/1/4
Y1 - 2021/1/4
N2 - Age-related sarcopenia constitutes an important health problem associated with adverse outcomes. Sarcopenia is closely associated with fat infiltration in muscle, which is attributable to interstitial mesenchymal progenitors. Mesenchymal progenitors are nonmyogenic in nature but are required for homeostatic muscle maintenance. However, the underlying mechanism of mesenchymal progenitor-dependent muscle maintenance is not clear, nor is the precise role of mesenchymal progenitors in sarcopenia. Here, we show that mice genetically engineered to specifically deplete mesenchymal progenitors exhibited phenotypes markedly similar to sarcopenia, including muscle weakness, myofiber atrophy, alterations of fiber types, and denervation at neuromuscular junctions. Through searching for genes responsible for mesenchymal progenitor-dependent muscle maintenance, we found that Bmp3b is specifically expressed in mesenchymal progenitors, whereas its expression level is significantly decreased during aging or adipogenic differentiation. The functional importance of BMP3B in maintaining myofiber mass as well as muscle-nerve interaction was demonstrated using knockout mice and cultured cells treated with BMP3B. Furthermore, the administration of recombinant BMP3B in aged mice reversed their sarcopenic phenotypes. These results reveal previously unrecognized mechanisms by which the mesenchymal progenitors ensure muscle integrity and suggest that age-related changes in mesenchymal progenitors have a considerable impact on the development of sarcopenia.
AB - Age-related sarcopenia constitutes an important health problem associated with adverse outcomes. Sarcopenia is closely associated with fat infiltration in muscle, which is attributable to interstitial mesenchymal progenitors. Mesenchymal progenitors are nonmyogenic in nature but are required for homeostatic muscle maintenance. However, the underlying mechanism of mesenchymal progenitor-dependent muscle maintenance is not clear, nor is the precise role of mesenchymal progenitors in sarcopenia. Here, we show that mice genetically engineered to specifically deplete mesenchymal progenitors exhibited phenotypes markedly similar to sarcopenia, including muscle weakness, myofiber atrophy, alterations of fiber types, and denervation at neuromuscular junctions. Through searching for genes responsible for mesenchymal progenitor-dependent muscle maintenance, we found that Bmp3b is specifically expressed in mesenchymal progenitors, whereas its expression level is significantly decreased during aging or adipogenic differentiation. The functional importance of BMP3B in maintaining myofiber mass as well as muscle-nerve interaction was demonstrated using knockout mice and cultured cells treated with BMP3B. Furthermore, the administration of recombinant BMP3B in aged mice reversed their sarcopenic phenotypes. These results reveal previously unrecognized mechanisms by which the mesenchymal progenitors ensure muscle integrity and suggest that age-related changes in mesenchymal progenitors have a considerable impact on the development of sarcopenia.
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U2 - 10.1172/JCI139617
DO - 10.1172/JCI139617
M3 - Article
C2 - 33170806
AN - SCOPUS:85098886064
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 1
M1 - e139617
ER -