TRPV4 deficiency increases skeletal muscle metabolic capacity and resistance against diet-induced obesity.
Transient receptor potential channel V4 (TRPV4) functions as a nonselective cation channel in various cells and plays physiological roles in osmotic and thermal sensation. However, the function of TRPV4 in energy metabolism is unknown. Here, we report that TRPV4 deficiency results in increased muscle oxidative capacity and resistance to diet-induced obesity in mice. Although no difference in body weight was observed between wild-type and Trpv4(-/-) mice when fed a standard chow diet, obesity phenotypes induced by a high-fat diet were significantly improved in Trpv4(-/-) mice, without any change in food intake. Quantitative analysis of mRNA revealed the constitutive upregulation of many genes, including those for transcription factors such as peroxisome proliferator-activated receptor α and for metabolic enzymes such as phosphoenolpyruvate carboxykinase. These upregulated genes were especially prominent in oxidative skeletal muscle, in which the activity of Ca(2+)-dependent phosphatase calcineurin was elevated, suggesting that other Ca(2+) channels function in the skeletal muscle of Trpv4(-/-) mice. Indeed, gene expressions for TRPC3 and TRPC6 increased in the muscles of Trpv4(-/-) mice compared with those of wild-type mice. The number of oxidative type I fiber also increased in the mutant muscles following myogenin gene induction. These results strongly suggested that inactivation of Trpv4 induces compensatory increases in TRPC3 and TRPC6 production, and elevation of calcineurin activity, affecting energy metabolism through increased expression of genes involved in fuel oxidation in skeletal muscle and thereby contributing to increased energy expenditure and protection from diet-induced obesity in mice.
Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan.
Tatsuya
T
Kusudo
Zhonghua
Z
Wang
Atsuko
A
Mizuno
Makoto
M
Suzuki
Hitoshi
H
Yamashita
D000818:Animals; D001831:Body Temperature; D001835:Body Weight / Q000502:physiology; D002153:Calorimetry, Indirect; D004032:Diet; D004734:Energy Metabolism / Q000235:genetics* / Q000502:physiology; D007150:Immunohistochemistry; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009246:NADH Tetrazolium Reductase / Q000378:metabolism; D009765:Obesity / Q000235:genetics*; D010084:Oxidation-Reduction; D060888:Real-Time Polymerase Chain Reaction; D050052:TRPC Cation Channels / Q000235:genetics; D000074287:TRPC6 Cation Channel; D050916:TRPV Cation Channels / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D013686:Telemetry; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D000074287:TRPC6 Cation Channel; D050916:TRPV Cation Channels; C492146:Trpc6 protein, mouse; C486576:Trpv4 protein, mouse; D009246:NADH Tetrazolium Reductase