TY - JOUR
T1 - METTL14 is required for exercise-induced cardiac hypertrophy and protects against myocardial ischemia-reperfusion injury
AU - Wang, Lijun
AU - Wang, Jiaqi
AU - Yu, Pujiao
AU - Feng, Jingyi
AU - Xu, Gui e.
AU - Zhao, Xuan
AU - Wang, Tianhui
AU - Lehmann, H. Immo
AU - Li, Guoping
AU - Sluijter, Joost P.G.
AU - Xiao, Junjie
N1 - Funding Information:
This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to J.J.X.), National Natural Science Foundation of China (82020108002 and 82225005 to J.J.X., 82270291 and 81800358 to L.J.W.), Innovation Program of Shanghai Municipal Education Commission (2017-01-07-00-09-E00042 to J.J.Xiao), the grant from Science and Technology Commission of Shanghai Municipality (21XD1421300 and 20DZ2255400 to J.J.X.), Natural Science Foundation of Shanghai (19ZR1474100 to L.J.W.), and the “Dawn” Program of Shanghai Education Commission (19SG34 to J.J.X.).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - RNA m6A modification is the most widely distributed RNA methylation and is closely related to various pathophysiological processes. Although the benefit of regular exercise on the heart has been well recognized, the role of RNA m6A in exercise training and exercise-induced physiological cardiac hypertrophy remains largely unknown. Here, we show that endurance exercise training leads to reduced cardiac mRNA m6A levels. METTL14 is downregulated by exercise, both at the level of RNA m6A and at the protein level. In vivo, wild-type METTL14 overexpression, but not MTase inactive mutant METTL14, blocks exercise-induced physiological cardiac hypertrophy. Cardiac-specific METTL14 knockdown attenuates acute ischemia-reperfusion injury as well as cardiac dysfunction in ischemia-reperfusion remodeling. Mechanistically, silencing METTL14 suppresses Phlpp2 mRNA m6A modifications and activates Akt-S473, in turn regulating cardiomyocyte growth and apoptosis. Our data indicates that METTL14 plays an important role in maintaining cardiac homeostasis. METTL14 downregulation represents a promising therapeutic strategy to attenuate cardiac remodeling.
AB - RNA m6A modification is the most widely distributed RNA methylation and is closely related to various pathophysiological processes. Although the benefit of regular exercise on the heart has been well recognized, the role of RNA m6A in exercise training and exercise-induced physiological cardiac hypertrophy remains largely unknown. Here, we show that endurance exercise training leads to reduced cardiac mRNA m6A levels. METTL14 is downregulated by exercise, both at the level of RNA m6A and at the protein level. In vivo, wild-type METTL14 overexpression, but not MTase inactive mutant METTL14, blocks exercise-induced physiological cardiac hypertrophy. Cardiac-specific METTL14 knockdown attenuates acute ischemia-reperfusion injury as well as cardiac dysfunction in ischemia-reperfusion remodeling. Mechanistically, silencing METTL14 suppresses Phlpp2 mRNA m6A modifications and activates Akt-S473, in turn regulating cardiomyocyte growth and apoptosis. Our data indicates that METTL14 plays an important role in maintaining cardiac homeostasis. METTL14 downregulation represents a promising therapeutic strategy to attenuate cardiac remodeling.
UR - http://www.scopus.com/inward/record.url?scp=85141538356&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-34434-y
DO - 10.1038/s41467-022-34434-y
M3 - Article
C2 - 36351918
AN - SCOPUS:85141538356
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6762
ER -