FTO is required for myogenesis by positively regulating mTOR-PGC-1α pathway-mediated mitochondria biogenesis.
Global germ line loss of fat mass- and obesity-associated (FTO) gene results in both the reduction of fat mass and lean mass in mice. The role of FTO in adipogenesis has been proposed, however, that in myogenesis has not. Skeletal muscle is the main component of body lean mass, so its connection with FTO physiologic significance need to be clarified. Here, we assessed the impact of FTO on murine skeletal muscle differentiation by in vitro and in vivo experiments. We found that FTO expression increased during myoblasts differentiation, while the silence of FTO inhibited the differentiation; in addition, skeletal muscle development was impaired in skeletal muscle FTO-deficient mice. Significantly, FTO-promoted myogenic differentiation was dependent on its m6A demethylase activity. Mechanically, we found that FTO downregulation suppressed mitochondria biogenesis and energy production, showing as the decreased mitochondria mass and mitochondrial DNA (mtDNA) content, the downregulated expression of mtDNA-encoding genes and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) gene, together with declined ATP level. Moreover, the involvement of mTOR-PGC-1α pathway in the connection between FTO and muscle differentiation is displayed, since the expression of FTO affected the activity of mTOR and rapamycin blocked FTO-induced PGC-1α transcription, along with the parallel alteration pattern of FTO expression and mTOR phosphorylation during myoblasts differentiation. Summarily, our findings provide the first evidence for the contribution of FTO for skeletal muscle differentiation and a new insight to study the physiologic significance of RNA methylation.
Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China.
Xiaobo
X
Wang
Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China.
Ning
N
Huang
Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China.
Min
M
Yang
Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China.
Dandan
D
Wei
Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China.
Haoran
H
Tai
Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China.
Xiaojuan
X
Han
Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China.
Hui
H
Gong
Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China.
Jiao
J
Zhou
Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China.
Jianqiong
J
Qin
Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China.
Xiawei
X
Wei
Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China.
Honghan
H
Chen
Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China.
Tingting
T
Fang
Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China.
Hengyi
H
Xiao
D000255:Adenosine Triphosphate / Q000378:metabolism; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000378:metabolism*; D000818:Animals; D053898:Biosynthetic Pathways / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology; D032446:Myoblasts / Q000378:metabolism / Q000502:physiology; D047495:PPAR gamma / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
D004272:DNA, Mitochondrial; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D000255:Adenosine Triphosphate; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases