The cytokine, interleukin-7 (IL-7), has essential growth activities that maintain the homeostatic balance of the immune system. Little is known of the mechanism by which IL-7 signaling regulates metabolic activity in support of its vital function in lymphocytes. We observed that IL-7 deprivation caused a rapid decline in ATP levels that were attributable to loss of intracellular glucose retention. To identify the transducer of the IL-7 metabolic signal, we examined the expression of three important regulators of glucose metabolism, the glucose transporter, GLUT-1, and two glycolytic enzymes, Hexokinase II (HXKII) and phosphofructokinase-1 (PFK1), using an IL-7-dependent T-cell line and primary lymphocytes. We found that in lymphocytes deprived of IL-7 loss of glucose uptake correlated with decreased expression of HXKII. Re-addition of IL-7 to cytokine deprived lymphocytes restored the transcription of the HXKII gene within 2 hours, but not that of GLUT-1 or PFK1. IL-7-mediated increases in HXKII, but not GLUT-1 or PFK-1, were also observed at the protein level. Inhibition of HXKII with 3-Bromopyruvate or specific siRNA decreased glucose utilization, as well as ATP levels, in the presence of IL-7, while over-expression of HXKII, but not GLUT-1, restored glucose retention and increased ATP levels in the absence of IL-7. This IL-7 mediated HXKII gene expression was abrogated with inhibition of JNK pathway. IL-7 also increased activation of AP-1 complex and DNA binding of JunD, a transcriptional complex thought to be negative regulator of proliferation. We found that over expression of HXKII caused cell cycle arrest and cell death, indicating that a potent IL-7 signal could produce negative growth signals. We conclude that IL-7 controls glucose utilization by regulating the gene expression of HXKII through activation of JNK-JunD pathway, suggesting a mechanism by which IL-7 supports bioenergetics that control cell fate decisions in lymphocytes.

Activation of AMP-activated protein kinase (AMPK) results in the upregulation of several intracellular systems which help to prepare a cell for a high energy challenge. The magnitude of the AMPK response to a 10 min bout of exercise has been found to decrease in red quadriceps (RQ) following training, while putative AMPK roles seem to be maintained; specifically, the biogenesis of mitochondria and higher levels of hexokinase II and glucose transporter 4 (GLUT4). If the AMPK response to exercise is responsible in part for these adaptations, how can they be maintained if the AMPK response is attenuated? The purpose of this study was to determine whether phosphorylation of AMPK in RQ increases during 2-hr training bouts after rats have trained for 8 wks. Male Sprague-Dawley rats ran up to 30 m/min up a 15% grade, 2 hr/day for 8 wks. On the final bout of exercise, trained rats ran for 0 (TRC), 30 (TR1), or 120 min (TR2) up a 15% grade at 30 m/min. Red quadriceps (RQ), soleus, and white quadriceps (WQ) were immediately collected and frozen for analysis. Citrate synthase activity increased in RQ (79 ± 3 vs. 37 ± 4 µmol/g/min) and soleus (64 ± 4 vs. 35 ± 2 µmol/g/min) but not in WQ compared to non-trained controls. In trained rats, maximal increases in T-172 phosphorylation of AMPK occurred after 30 min of exercise (relative values = 1.29 ± 0.06 vs. 1.00 ± 0.06). AMPK phosphorylation did not change significantly in trained rats that ran for 2 hrs (1.31 ± 0.09) compared to rats that ran for 30 min. Similarly, maximal increases in AMPK activity in trained rats occurred after 30 min of exercise (pmoles/min/mg = 2.67 ± .05 vs. 1.09 ± .41) and AMPK activity did not change significantly in trained rats that ran for 2 hrs (2.79 ± .17) compared to rats that ran for 30 min. Previous studies demonstrated a 2−3 fold increase in AMPK activity in non-trained rats after 30 min of exercise at lower work rates. These results demonstrate that the AMPK response to exercise is attenuated even after two-hr bouts of exercise. This implies that the increase in mitochondrial oxidative enzymes, GLUT4, and hexokinase II may be maintained by signals other than the AMPK signaling system. The CREB signaling pathway is one such system. Western analysis of phospho-CREB (Ser133) showed a statistically significant increase in phospho-CREB content in trained rats relative to control. No change in phospho-CREB protein expression was observed between TRC, TR1, and TR2 rats. Significant increases of muscle phospho-CREB content in TRC relative to untrained rats suggest that CREB remains phosphorylated in trained rats even after 24 hrs of rest. Accordingly, chronically increased phospho-CREB in muscle of trained rats relative to controls may explain in part how increased levels of mitochondria are maintained in the face of reduced AMPK response. Alternatively, the attenuated AMPK response may still be above the threshold required for inducing adaptations to endurance training.

REDD1 contribue au dialogue entre le métabolisme énergétique et la masse musculaire.REDD1 est une protéine ubiquitaire et conservée qui est exprimée en réponse à de nombreux stress et pathologies associés à une atrophie du muscle squelettique, un paramètre corrélé à la mortalité des patients. REDD1 est connue pour inhiber la voie Akt/mTORC1 qui contrôle la synthèse des protéines (composants majoritaires du muscle), mais également d'autres macromolécules tels les ribosomes, les nucléotides ou le glycogène. Nos travaux montrent, grâce à un modèle murin, que REDD1 est capable d'une part d'inhiber la synthèse protéique ce qui conduit à l'atrophie du muscle, et d'autre part de réduire le stockage du glycogène musculaire. Cependant, sa délétion est responsable d'une augmentation du métabolisme basal, d'une réduction de la capacité d'exercice et d'une aggravation de l'atrophie musculaire en situation d'hypoxie. Ces altérations du métabolisme ne sont pas liées à un dysfonctionnement mitochondrial, mais associées à une moindre inhibition de la signalisation d'Akt et/ou mTORC1, tous deux responsables de l'activation de processus anaboliques couteux en énergie. Pris ensembles, ces résultats suggèrent que REDD1 agit comme modérateur de la dépense en ATP dans des situations de stress énergétique. / REDD1 contributes to the crosstalk between energetic metabolism and skeletal muscle mass. REDD1 is a ubiquitous and conserved protein, which is expressed in response to numerous stresses and pathologies responsible of muscle atrophy, a parameter correlated with patient mortality. REDD1 is known to inhibit Akt/mTORC1 pathway which controls synthesis of proteins (the major component of muscle) and other macromolecules such as ribosome, nucleotide or glycogen. Our work shows on a mice model that REDD1 inhibits protein synthesis, leading to skeletal muscle atrophy, and reduces muscle glycogen storage. However, REDD1 deletion is responsible of an increase in basal metabolism, a reduction of exercise capacity and an exacerbation of hypoxia-induced skeletal muscle atrophy. These metabolic alterations are not associated with a mitochondrial dysfunction but rather with an hyper activation of the Akt/mTORC1 pathway which is responsible for the stimulation of energy demanding processes. Altogether, these results strongly suggest that REDD1 acts for moderating ATP demand in energetic stress conditions