Equipe 2 : « Régulation of Muscle Mass and Metabolic Disorders »

CarMeN’ Team 2 gathers scientists and clinicians to work on the regulation of muscle mass and muscle homeostasis in relation to energetic disorders and metabolic diseases, such as obesity and diabetes. We are working on the hypothesis that muscle tissue response to environmental and lifestyle changes (e.g. sedentary behavior, physical activity and nutrition) impacts health status (obesity, insulin resistance, type 2 diabetes as well other factors involved in the development of cardiovascular risk).


Our research strategies focus on:

  • Identification of the events sequence and the signals that link sedentary behavior with muscle dysfunction and affect health, using a top-down approach from whole-body level to molecular pathways (real-life phenotyping, novel imaging methodologies, stable isotope metabolic measurement, micro-biopsies for tissue investigations, genomic and histology analyses) –

        Principal Investigator: Chantal SIMON (PU-PH)


  • Characterization of the role of extracellular vesicles released from skeletal muscle in inter-organ cross talks and in muscle physiology (exosomes, exosomal miRNAs, and use of circulating miRNAs as biomarkers of whole-body homeostasis)-

         Principal Investigator: Sophie ROME (DR INRA)

Ongoing Research projects


  1. In vivo modulation of sedentary behavior and physical activity to study muscle homeostasis and metabolic health outcomes (PI: Chantal SIMON)

Several exploratory and interventional research studies are already developed or will be programmed, both in humans and in animal models, to investigate the role of skeletal muscle tissue in the energetic and metabolic adaptation to physical inactivity and sedentary behavior.

These programs benefit from all the expertise and facilities that have been developed by/or in collaboration with our team (real-life phenotyping, novel imaging methodologies, stable isotope metabolic measurement, micro-biopsies for tissue investigations, genomic and histology facilities), which allow to investigate the consequences of physical activity and sedentariness modulation from whole-body level to cell biology.

1.a) Projects in humans

In human we use two main approaches to study energetic and metabolic adaptations to physical inactivity, and to test different counter-measures (physical activity protocols or nutritional): 1) free-living observational and interventional studies in various groups of normal subjects with contrasted fat mass phenotypes or in patients (e.g. obese, insulin-resistant and diabetic patients); 2) extreme conditions, e.g. terrestrial models of physiological changes in human spaceflights such as prolonged (up to 3 months) bed-rest studies with a six-degree head-down tilt to simulate weightless.

Exercise training improves fat metabolism in sedentary overweight men, but does not restore lean metabolic phenotype.  In the LIPOX study, we showed that 2 months of exercise training at 50% VO2peak (according to current guidelines) improved aerobic fitness, insulin sensitivity and fat oxidation (measured by [d31]palmitate and [1-(13)C]oleate mixed in standard meals). This latter was explained by a coordinated response at the muscle level enhancing fat uptake, acylation and oxidation rather than by changes in dietary fat trafficking. However, the training did not restore the lean metabolic phenotype in overweight adults, likely due to a spontaneous reduction in non-training activity related energy expenditure (accelerometry and doubly labeled water) that partially compensated the training effects. These data support the crucial role of all the physical activity components, including those of low intensity, for fat and energetic balance (E.Lefai et al, Int. J. Obes. 2017).

A nutrient cocktail as an antidote to sedentary behavior. In the COCKTAIL study, we examined the capacity of a nutrient cocktail with anti-inflammatory and anti-oxidant properties to prevent the expected metabolic alterations of induced physical inactivity and sedentary behaviour. Healthy trained men were randomly divided into a control group (no supplementation) and a cocktail group for a 20-day free-living intervention during which they stopped exercise, decreased their daily steps and were submitted to a 10-day fructose overfeeding. We showed that the nutrient cocktail prevented the alterations in lipid metabolism including de novo lipogenesis (measured by means of labelled fructose), the decrease in type-IIa muscle fiber cross-sectional area, the increase in protein ubiquitination content, and improved the circulating anti-oxidant capacity, while it did not prevent the decrease in insulin sensitivity and its muscular correlates (Damiot A. et al, J.Appl.Physiol.2018).

Bed-Rest Studies (supported by CNES and ESA, the French and European Spatial Agencies). Using a mid-term bed-rest protocol with showed that 21 days of severe physical inactivity, with or without whey protein supplementation, decreased the ability to switch from fat to carbohydrate oxidation when transitioning from fasted to fed states (i.e. metabolic inflexibility), anti-oxidant capacity, fat-free mass, and muscle insulin sensitivity along with greater fat deposition in muscle. Importantly, physical inactivity triggered metabolic inflexibility, even if energy balance was maintained. These data support the role of physical inactivity in metabolic inflexibility, and we further showed that muscle alterations and metabolic inflexibility preceded systemic glucose intolerance (F.Rudwill, J.Clin.Endocrinol. Metab., 2018).

The long-term bed-rest (60-days) conducted in Toulouse in 2017 (ESA AO13-BR CNES 2015-2018) will allow us to better delineate the mechanisms and the temporal sequence of events by which severe and prolonged sedentary behavior in humans leads to ectopic fat storage and insulin resistance. We will also test if the preventive effects of the nutrient cocktail observed in the free-living COCKTAIL study are maintained during a more severe and longer physical inactivity period.

TRANSITION, an ongoing longitudinal study of the Fulani people, an ancestral population of nomad pastoralists living in the Ferlo, a Sahelian region in northern Senegal, aims to better understand the respective role of biological and environmental factors on body weight regulation, a question that remains one of the most debated research topics. During the last decades, part of the Fulanis progressively sedentarised in small cities around boreholes built to facilitate access to water, while others remained in camps spread across the savanna, some being more than 30 km of walking distance from water. The recent coordinated construction of the Great Green Wall is expected to further amplify this ecological transition in the next few years and thus offers an exceptional opportunity to track in real-time the behavioral, social and biological changes induced by an epidemiological transition. In collaboration with the OHMi Tessékéré (Sénégal) and the IPHC (Strasbourg), we will follow 400 Fulanis facing different anthropo-socio-ecological constraints to dissect the respective role of diet, physical activity and lifestyles on long-term regulation of adiposity and biomarkers of health.

1.b) Projects in animals

Hibernatus: Hibernating bear has developed specific adaptations to preserve its skeletal muscle tissue during extended periods of disuse and starvation, two conditions that are known to trigger immediate and massive muscle atrophy in humans and laboratory rodent models. The bear’s ability to muscle functionality contrasts dramatically with the wealth of studies demonstrating the generallossof skeletal muscle mass and strength that is generally observed in response to inactivity.

ours 2






Within a large collaborative European program, our team is focusing on the identification of specific compounds in winter bear serum, able to positively regulate muscle homeostasis. For this purpose, serum from bears collected in summer (non-hibernating) or in winter (hibernating) is tested for their ability to modify the protein balance, the metabolism and the phenotype of cultured muscle cells (Giroud S. et al, Scient. Rep., in press; Chanon S., J Vis Exp 2017). This work is presently developed by E. Lefai in his new laboratory in Clermont-Ferrand, in collaboration with our team.

  1. Role of extracellular vesicles released from skeletal muscle and the other insulin-sensitive tissues (PI: Sophie Rome)

2.a) Extracellular vesicles and inter-organ cross talk.

Extracellular vesicles from quadriceps (S. ROME personal communication)

Long distance transmission of signals between tissues is commonly believed to be associated to protein-based signaling systems as hormones and cytokines. In this context, skeletal muscle (SkM)-secreted proteins have been shown to play an important role in intercellular communications. Recently, we have demonstrated that muscle cells release membranous bioactive extracellular vesicles (EVs) (exosomes, macroparticles and apoptotic bodies) which transfer both proteins and functional miRNAs between cells resulting in the regulation of specific signalling pathways in recipient cells (Forterre et al. 2014a/b, Aswad et al. 2016). We have also found that insulin-resistance induced by lipid-enriched diet, was associated with an increase in SkM-released EVs that were able to transfer the deleterious effects of palmitate between muscle cells (Aswad et al. 2014). Finally, we have provided a proof-of-concept that SkM-released EVs transmit signals to the pancreas during the development of insulin-resistance (Jalabert et al. 2015).


Ongoing projects :

-Relationship between insulin-resistance and multivesicular body formation ?

-Relationship between multivesicular body formation and insulin-signaling ?

-Characterisation of the subpopulations of extracellular vesicles released from muscle cells

-Creation of the French Society for extra cellular vesicles

2.b) Extracellular vesicles and miRNAs as biomarkers of whole body homeostasis

It has become clear that sedentary behaviour and obesity have multiple known, and likely unknown, physiological impacts which are not easily addressed by single-gene, protein or metabolite approaches. Therefore, a combination of all genomic-based data may be necessary to detect the full metabolic consequences of sedentary behavior and associated diseases, or to monitor the impact of lifestyle interventions. Circulating miRNA concentration are good biomarkers for cancers, neurological disorders and metabolic diseases and thus we have tested whether they could reflect either the early phases of metabolic stress or the development of metabolic syndrome associated with physical inactivity or obesity.

Ongoing projects :

-Quantification of circulating miRNAs during lifestyle interventions

-Determination of the most relevant biofluid for miRNA profiling in diabetic subjects

-Role of circulating miRNA in the developpement of obesity-associated complications

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Responsables de l’Equipe 2
SIMON Chantal PUPH chantal.simon@univ-lyon1.fr

Membres de l’Equipe 2

BONNEFOY Marc PUPH marc.bonnefoy@chu-lyon.fr
CHANON Stéphanie IE stephanie.chanon@univ-lyon1.fr
CHIKH Karim MCUPH karim.chikh@univ-lyon1.fr
COLOSETTI Pascal IR pascal.colosetti@inserm.fr
EUTHINE Vanessa IE vanessa.euthine@sante.univ-lyon1.fr
GARNOTEL Mael PhD mael.garnotel@gmail.com
JALABERT Audrey TR audrey.jalabert@inra.fr
ROBERT Maud PUPH maud.robert@chu-lyon.fr
ROME Sophie DR2 srome@univ-lyon1.fr
VIEILLE MARCHISET Aurélie TR aurelie.vieille-marchiset@lyon1.fr


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