Effects of FoxO1 on Gene Expression in Skeletal Muscle

Zapater, Joseph; Zhang, Wenwei; Unterman, Amy; Larsen, Peter; Kamei, Yasumoto; Miura, Shinji; Ezaki, Osamu; Unterman, Terry
June 2007
Diabetes;Jun2007 Supplement 1, Vol. 56, pA288
Academic Journal
FoxO transcription factors are major targets of insulin action and contribute to the adaptation to nutrient restriction. Previous studies in muscle indicate that FoxO1 promotes atrophy through the induction of atrogin-1, and stimulates expression of lipoprotein lipase and PDK4. To further examine the role of FoxO proteins in muscle, we performed gene army studies in transgenic mice expressing constitutively active FoxO1 in skeletal muscle (TGN) (JBC 279:41114, 2004) and wild type controls (WT) after a 24 hr fast and 6 hr after a high carb meal, when insulin levels are high and the function of endogenous FoxO proteins (but not the constitutively active transgene) is suppressed. Studies were performed with RNA from 5-8 animals in each group, and RNA from muscles enriched in Type 1 (soleus [Sol]) or Type 2 (anterior tibialis [AT]) fibers were analyzed separately. Gene army studies with Affymetrix Mouse Genome 430 2.0 arrays (45037 probe sets) were performed by standard Affymetrix protocols in the UIC Genomics Core Facility. Differentially expressed transcripts were identified by local pooled error, raw p-values were corrected for a false discovery rate of <0.05, and transcripts that were differentially expressed by <10% were excluded. Results show that the effect of constitutively active FoxO1 is more marked in Sol compared to AT (1437 vs 1038 genes affected), suggesting that FoxO effects are more pronounced in Type 1 muscle fibers. However, FoxO1 regulated genes in Sol are not limited to those that are differentially expressed in Sol vs. AT in WT, indicating that effects of FoxO are not due solely to a shift in fiber type. Effects of FoxO1 also are not limited to genes which are rapidly regulated by feeding in Sol (389) or AT (282), suggesting that FoxO proteins also may mediate long-term effects of nutrition in muscle. In Sol, FoxO1 reduces expression of multiple genes involved in glucose and lactate metabolism, indicating that FoxO proteins may spare glucose for utilization by other tissues and lactate as a source for gluconeogenesis. FoxO1 also alters expression of multiple genes involved in beta-oxidation, electron chain transport activity, mitochondrial transport, myoglobin and heme synthesis, indicating that FoxO modulates oxidative metabolism in muscle in multiple ways. Together, these results indicate that FoxO proteins exert multiple effects on energy metabolism in skeletal muscle that contribute to the adaptation to nutrient restriction and when insulin signaling is impaired.


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