Projet ANR-07-BLAN-0354 – MetUCP3 : Metabolic alterations associated with UCP3 gene expression in skeletal muscle
Programme : Blanc (BLANC) 2007
Année de financement : 2007
Coordinateur du projet : Monsieur Benoît GIANNESINI (CNRS DELEGATION REGIONALE PROVENCE ET CORSE)
Partenaires : Centre national de la recherche scientifique
Montant : 303800.0 euros
Date de début : 2007
Durée : 36 mois
Résumé : Uncoupling proteins (UCPs) are inner mitochondrial membrane transporters that dissipate the proton gradient generated throughout the respiratory chain into heat. UCPs are then important potential determinants of metabolic efficiency and may play critical roles in body weight maintenance and thermoregulation. UCP3 is highly and preferentially expressed in skeletal muscle and would play a major role in whole body epinephrine-induced thermogenesis and energy expenditure and its regulation. UCP3 could significantly contribute to muscle energetics through its involvement in proton gradient dissipation. It is noteworthy that UCP3 could also promote fatty acid oxidation in skeletal muscle by acting as a mitochondrial fatty acid anion transporter. Overall, UCP3 gene expression may contribute to energy dissipation at the mitochondrial level, and would have a key role in the regulation of thermogenesis, energy efficiency and body mass. Considering the potential role of UCP3 in body metabolism, it is of interest to investigate the physiological function of UCP3 in an integrative approach in vivo. This issue has actually been very scarcely addressed. In vivo 31P-MRS experiments suggest that the efficiency of mitochondrial ATP synthesis is improved in UCP3-knockout mice. However, this improvement was inconsistent with the lack of phenotypic changes in whole body energy metabolism and thermoregulation. Conversely, the enhancement of UCP3 expression was linked to a decreased mitochondrial energy coupling. -  We have recently shown that a single administration of capsiate (a non pungent compound extracted from a sweet pepper) significantly downregulates UCP3 gene expression in rat muscle and enhances aerobic energy production at rest and during exercise. These changes were not associated to any improvement in force-generating capacity suggesting the contribution of additional non contractile ATP-consuming process(es) which should be further investigated. In mice, capsiate administration has been previously reported to increase UCP3 gene expression in addition to alteration in body energy metabolism. Capsiate ingestion increases the body temperature and basal oxygen consumption in resting humans, hence suggesting that this compound promotes thermogenesis and energy consumption. Further, a two-week daily capsiate administration suppressed body fat accumulation in mice. This increased energy metabolism was accompanied by a transient increase in the expression of mitochondrial uncoupling proteins UCP3. -  Overall, the metabolic modifications associated with UCP3 expression are still unclear particularly in relation to muscle energy consumption and fat metabolism. In mice, oral administration of capsiate increases UCP3 gene expression, promotes both thermogenesis and basal oxygen consumption. In rat, a single oral administration of capsiate significantly reduces UCP3 gene expression, increases oxidative ATP production and phosphocreatine level at rest and during exercise. These data are in favour of a potential effect of capsiate on basal and muscle energy metabolism. However, the cause-to-effect relationships between capsiate-induced changes in UCP3 gene expression and muscle energy metabolism requires further investigations. -  The aim of the present project is to determine the effects of acute and chronic oral administrations of capsiate both in rat and mice through an integrative approach investigating muscle energy metabolism, muscular performance, whole body fatty acid metabolism, UCP3 gene expression and mitochondrial electron chain transport in skeletal muscle at rest and during muscle activity. We will use an original experimental setup allowing a strictly non-invasive investigation of skeletal muscle function in situ using magnetic resonance techniques and measurements of muscle performance during exercise. Whole body fatty acid metabolism will be investigated through measurements of body fat accumulation using MRI and plasmatic level of