Contact:  Didier Rémond

CONTEXT

Loss of mobility and cognitive decline are the main causes of the loss of autonomy of individuals, a subject of particular concern in the context of aging. Maintaining an active musculoskeletal system for as long as possible therefore has a major influence on health and quality of life. This has become a priority target so that the extension of life expectancy currently observed can be achieved under the best possible conditions, without disability. Every component of the musculoskeletal system is affected by ageing. The muscle, affected by sarcopenia, progressively loses mass and functionality. The bone, affected by osteopenia, defined as moderate bone demineralization, intermediate between normal bone and osteoporosis. The joints, with the onset of painful chronic inflammatory diseases.

Nutrition, physical activity and management of chronic pain are the main levers for maintaining the functionality of the musculoskeletal system. Advances in the knowledge of the mechanisms involved in the development of sarcopenia, osteopenia, inflammation and pain now make it possible to propose innovative strategies in each of these areas. However, many grey areas remain in this knowledge, justifying the use of increasingly sophisticated exploration models (genetically modified rodents, molecular imaging, etc.). Even if sarcopenia can be described as a slow erosion of muscle mass, it is known that this process is not linear. As we age, it becomes increasingly difficult to recover the muscle mass lost during catabolic states (infections, immobilization ...), and the succession of catabolic crises will accelerate the erosion process. Limiting muscle wasting during these states is therefore a major challenge.

Beyond research on the sensu-stricto locomotor system, it now seems that new actors must be taken into account in the study of the nutrition-locomotor apparatus nexus. Indeed, several articles suggest a possible role of the intestinal microbiota in the evolution of sarcopenia and osteopenia, and the existence of an intestine-muscle axis through which the microbiota could act as a mediator of the nutrition-locomotor apparatus relationship. One of the explanatory links in this relationship could be systemic inflammation. Finally, it is now clear that alterations in osteo-muscular metabolism are not sufficient to fully explain the decline of the musculoskeletal system. Indeed, the metabolism of other organs, by decreasing the bioavailability of key nutrients for the musculoskeletal system, or by releasing molecules negatively affecting its metabolism, can aggravate muscle wasting and bone demineralization. The integration of the metabolisms of the main compartments of the organism, under different feeding conditions and different pathophysiological situations thus becomes crucial for the development of corrective pharmaco/nutritional strategies.

OBJECTIVES

The NexN-Mob project pursues a dual objective, fully in line with the CAP20-25 project strategy, 1/ the implementation of a new platform for the in vivo study of metabolisms in relation to locomotor function, and 2/ the exploration of new concepts in the prevention and management of locomotor disorders associated with ageing.

The scientific project is based on 3 research axes, which will be supported by 3 research grants. In terms of results, axis 1 will provide knowledge on intra-organ metabolism (muscle, viscera) and inter-organ regulation, during catabolic states, in order to optimize the implementation of pharmaco/nutritional strategies to preserve muscle tissue. Axis 2 will provide new knowledge on the role of the microbiota in intestinal homeostasis and its repercussions at the level of the central nervous system, and ultimately on well-being and spontaneous activity. Axis 3 will provide knowledge on the role of the intestinal microbiota in the development of muscular disorders, by investigating more specifically the role of low-level systemic inflammation.

Doctoral grant 1: Deregulation of food intake during catabolic states: role of eIF2a/ATF4 signalling (UNH-Proteostasis)

Doctoral grant 2: Study of disturbances of the intestinal microbiota in case of Enterobacteriaceae infection: Consequences on behaviour and well-being (NeuroDOL / M2iSH)

Post-Doctoral Allocation : Fatigue and muscle wasting: Is tryptophan and its endogenous and microbial metabolites the key? (UNH-iMPROVINg / MEDIS)

The project is an opportunity to deploy on the Clermont site a new infrastructure dedicated to the in vivo investigation of metabolism. This will include a rodent animal facility with an EOPS (Free of Specific Pathogenic Organisms) module, to enable the production or import of knock-in, knock-out or transgenic mouse models under good conditions, associated with a standard module enabling long-term nutritional interventions to be carried out on rodents as they age (whether genetically modified or not). It will also include the development of an animal facility for minipigs, which, coupled with an already existing surgery room, will make it possible to study dynamically the postprandial metabolism of the various organs, in different physiopathological situations, by combining nutritional interventions and physical activity. These animal facilities will complement the Metabolism Exploration Platform (mass spectrometry platform, member of the MetaboHub national network).  

PARTNERSHIP

UMR1019 INRAE-UCA UNH (Unité de Nutrition Humaine)

UMR 454 INRAE-UCA MEDIS (Microbiologie, Environnement Digestif et Santé)

UMR 1107 INSERM/UCA NeuroDOL

UMR 1071 INSERM/UCA M2iSH (Microbes Intestin Inflammation et Susceptibilité de l'Hôte)

The Nex-N-Mob project is part of the actions carried out to federate the research forces of the Clermont-Ferrand site around the issue of nutrition-microbiota-mobility. It will enable new concepts to be explored and, at the end of the project, an operational infrastructure will be available to test and validate them.