TFE3 regulates muscle metabolic gene expression, increases glycogen stores, and enhances insulin sensitivity in mice.
The role of transcription factor E3 (TFE3), a bHLH transcription factor, in immunology and cancer has been well characterized. Recently, we reported that TFE3 activates hepatic IRS-2 and hexokinase, participates in insulin signaling, and ameliorates diabetes. However, the effects of TFE3 in other organs are poorly understood. Herein, we examined the effects of TFE3 on skeletal muscle, an important organ involved in glucose metabolism. We generated transgenic mice that selectively express TFE3 in skeletal muscles. These mice exhibit a slight acceleration in growth prior to adulthood as well as a progressive increase in muscle mass. In TFE3 transgenic muscle, glycogen stores were more than twofold than in wild-type mice, and this was associated with an upregulation of genes involved in glucose metabolism, specifically glucose transporter 4, hexokinase II, and glycogen synthase. Consequently, exercise endurance capacity was enhanced in this transgenic model. Furthermore, insulin sensitivity was enhanced in transgenic mice and exhibited better improvement after 4 wk of exercise training, which was associated with increased IRS-2 expression. The effects of TFE3 on glucose metabolism in skeletal muscle were different from that in the liver, although they did, in part, overlap. The potential role of TFE3 in regulating metabolic genes and glucose metabolism within skeletal muscle suggests that it may be used for treating metabolic diseases as well as increasing endurance in sport.
Department of Internal Medicine, Faculty of Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan.
Hitoshi
H
Iwasaki
Ayano
A
Naka
Kaoruko Tada
KT
Iida
Yoshimi
Y
Nakagawa
Takashi
T
Matsuzaka
Kiyo-aki
KA
Ishii
Kazuto
K
Kobayashi
Akimitsu
A
Takahashi
Shigeru
S
Yatoh
Naoya
N
Yahagi
Hirohito
H
Sone
Hiroaki
H
Suzuki
Nobuhiro
N
Yamada
Hitoshi
H
Shimano
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008112:Liver Glycogen / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D010805:Physical Conditioning, Animal / Q000502:physiology; D010807:Physical Endurance / Q000502:physiology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051275:Glucose Transporter Type 4; D008112:Liver Glycogen; C069203:TFE3 protein, human; D012313:RNA; D006006:Glycogen Synthase; D006593:Hexokinase; D005947:Glucose