Skeletal Muscle FOXO1 (FKHR) Transgenic Mice Have Less Skeletal Muscle Mass, Down-regulated Type I (Slow Twitch/Red Muscle) Fiber Genes, and Impaired Glycemic Control
Open Access
- 1 September 2004
- journal article
- Published by Elsevier BV in Journal of Biological Chemistry
- Vol. 279 (39), 41114-41123
- https://doi.org/10.1074/jbc.m400674200
Abstract
FOXO1, a member of the FOXO forkhead type transcription factors, is markedly up-regulated in skeletal muscle in energy-deprived states such as fasting and severe diabetes, but its functions in skeletal muscle have remained poorly understood. In this study, we created transgenic mice specifically overexpressing FOXO1 in skeletal muscle. These mice weighed less than the wild-type control mice, had a reduced skeletal muscle mass, and the muscle was paler in color. Microarray analysis revealed that the expression of many genes related to the structural proteins of type I muscles (slow twitch, red muscle) was decreased. Histological analyses showed a marked decrease in size of both type I and type II fibers and a significant decrease in the number of type I fibers in the skeletal muscle of FOXO1 mice. Enhanced gene expression of a lysosomal proteinase, cathepsin L, which is known to be up-regulated during skeletal muscle atrophy, suggested increased protein degradation in the skeletal muscle of FOXO1 mice. Running wheel activity (spontaneous locomotive activity) was significantly reduced in FOXO1 mice compared with control mice. Moreover, the FOXO1 mice showed impaired glycemic control after oral glucose and intraperitoneal insulin administration. These results suggest that FOXO1 negatively regulates skeletal muscle mass and type I fiber gene expression and leads to impaired skeletal muscle function. Activation of FOXO1 may be involved in the pathogenesis of sarcopenia, the age-related decline in muscle mass in humans, which leads to obesity and diabetes.Keywords
This publication has 58 references indexed in Scilit:
- The IGF-1/PI3K/Akt Pathway Prevents Expression of Muscle Atrophy-Induced Ubiquitin Ligases by Inhibiting FOXO Transcription FactorsMolecular Cell, 2004
- Overexpression of Peroxisome Proliferator-activated Receptor γ Coactivator-1α Down-regulates GLUT4 mRNA in Skeletal MusclesPublished by Elsevier BV ,2003
- Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stressNature, 2002
- Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1Biochemical Journal, 2002
- Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibresNature, 2002
- Ligand-dependent Interaction of Estrogen Receptor-α with Members of the Forkhead Transcription Factor FamilyPublished by Elsevier BV ,2001
- Differential Regulation of Endogenous Glucose-6-Phosphatase and Phosphoenolpyruvate Carboxykinase Gene Expression by the Forkhead Transcription Factor FKHR in H4IIE-Hepatoma CellsBiochemical and Biophysical Research Communications, 2001
- Regulatory Elements Governing Transcription in Specialized Myofiber SubtypesPublished by Elsevier BV ,2001
- A CBP Integrator Complex Mediates Transcriptional Activation and AP-1 Inhibition by Nuclear ReceptorsCell, 1996
- A Metachromatic Dye-Atpase Method for The Simultaneous Identification of Skeletal Muscle Fiber Types I, IIA, IIB and IICStain Technology, 1990