ACTUAL POSITION: DR2 INSERM
RESEARCH AREA: Molecular biology, Metabolic diseases
EDUCATION: 1979 and 1986: PhD and Doctorat ès Sciences,Lille University, France
ACTIVITIES: INSERM since 1983
1986-1988: Post doctoral fellow, Bearsden Institute; Molecular Carcinogenesis Glasgow, UK
1994-1995: EC research fellow, human capital and mobility program on imprinting, Babraham Institute Cambridge UK.
1997: Research position in UPR CNRS 514 Institute Cochin, Identification of LEPROT Paris.
RESEARCH AND CONGRESS PARTICIPATION:
Total of: 49 publications including Cell-1990 in first author position, EMBO J-1992, FASEB J-1993 and JCI-2009 in last author position, 1 patent, 5 invited talks, and 4 communications on LEPROT field.
Skeletal muscle metabolism is the major determinant of energy expenditure and defects in skeletal muscle oxidative metabolism have been implicated in numerous metabolic pathologies, including insulin resistance, glucose intolerance, and obesity. Nutritional behaviours, physical activity and ageing have been described as modulator of skeletal muscle mass, metabolic properties and oxidative capacity which results in muscle myofiber composition remodelling. Mitochondrial activity, which helps to maintain lipid and glucose homeostasis, clearly impact skeletal muscle plasticity. Prolonged calorie restriction (CR) induces skeletal muscle properties adaptations, leading to increased running endurance. In addition, it is well known that CR modifies the somatotropic axis and increases life span. Oxidative stress reduction, resulting from an increased mitochondrial activity, has been described as one of the actor involved in processes responsible for CR beneficial effects on life span. In the course of CR, the liver becomes growth hormone-resistant inducing an inhibition of the STAT5 signalling pathway leading to decreased IGF1 plasmatic level. We have recently shown that this mechanism involves two recently identified proteins, LEPROT and LEPROTL1, implicated in the reduction of cell surface GHR abundance. GHR -/- and IGFR+/- knockout mice and GH deficient Ames dwarf mice have increase longevity. However, GHR is necessary to CR-induced life span increased. In this nutritional condition, GH and GHR are still functional, in particular, in muscle to preserve proteins from catabolism and to decrease mobilisation of carbohydrate fuels. There are some data suggesting that GH may increase oxidative capacities in muscle. Potential molecular target for metabolic syndrome pharmacological treatment involved in CR-induced muscle plasticity, endurance to exercise and also longevity, are to date missing.
Recent studies in our laboratory, on transgenic mice for homologous hLEPROT and hLEPROTL1 over-expression revealed that hLEPROTL1 induces fast/glycolytic muscle atrophy associated with a switch toward slow/oxidative Myosine Heavy Chain (MHC), a key marker of muscle phenotype transitions. In addition, LEPROTL1 mice exhibit a reduced respiratory quotient and a greater endurance capacity during exercise, suggesting that these mice present an increased skeletal muscle oxidative capacity. Similar switch in muscle metabolism and increase in endurance is observed in wild type mice during CR. Using an in vitro muscular cell model, LEPROTL1-induced increased mitochondrial respiration has been confirmed. This data demonstrates a direct effect of LEPROTL1 at muscle cellular level.
The aim of the project is to investigate the molecular mechanism implicated in increased mitochondrial respiratory activity, oxidative capacity and consequently to metabolic muscle changes observed in LEPROTL1 mice, in particular the implication of LEPROTL1 in muscle GHR signalling. We will also study LEPROTL1 activation mechanism during CR.