Gilles CARNAC CV Gilles Carnac CRCN CNRS/PhD Biochemistry and Molecular Biology

Course and current status

On January 1, 2021: I joined the “Acquired Myopathies in Patients with Organ Deficiencies” team led by Pr Stéfan Matecki in the PhyMedExp INSERM U1046 CNRS UMR 9214 unit led by Dr. Alain Lacampagne.   

On January 1, 2011: We were recognized as an INSERM team "Dysfunctions of the skeletal muscle in acquired and hereditary pathologies" in the PhyMedExp INSERM U1046 CNRS UMR 9214 unit headed by Pr Jacques Mercier.  

On January 1, 2007. I joined the INSERM ERI 25 "Muscle and pathologies" team of Professor J Mercier, Building "Crastes de Paulet" Montpellier University Hospital.

March 2003 – January 2006: head of the “Adult muscle cells and FacioScapuloHumeral dystrophy” group. Laboratory: Center for Research in Macromolecular Biochemistry (CRBM) CNRS FRE 2593 1919 route de mende 34293 Montpellier cedex 5.

Since 2001 CR1 CNRS. Laboratory: Drs A. Fernandez, cell proliferation and differentiation laboratory, IGH, CNRS UPR 1142, Montpellier, France.

October 1998-March 2003: Permanent position CR CNRS1998-2001: CR2 CNRS; since 2001 CR1 CNRS.

November 1996-October 1998: Post-Doctoral Fellow Laboratory: Drs A. Fernandez, cell proliferation and differentiation laboratory, IGH, CNRS UPR 1142, 141 route de la cardonille, 34396 Montpellier cedex 5.

March 1994-November 1996: Post-Doctoral fellow Laboratory: Pr J.B. Gurdon, Wellcome/CRC Institute, Cambridge (England)

1990-1994: Thesis in Biochemistry and Molecular Biology Defended on January 28, 1994 at the University of Montpellier 2. Laboratory: Dr.A.Bonnieu, Cellular differentiation, INRA 2 place P.Viala, 34060 Montpellier cedex1.





Scientific summary

The regenerative capacity of skeletal muscle in degenerative muscle diseases is limited due to intrinsic stem cell defects and a deleterious microenvironment. Our ambition is to optimize the survival and differentiation of myogenic stem cells to restore the integrity of skeletal muscle.

Keywords: skeletal muscle, regeneration, stem cells, antioxidants, anabolic, plants.

When skeletal muscle fiber is damaged, satellite cells, adult muscle stem cells, are activated and repair the muscle tissue. These cells can be purified and cultured ex vivo, in order to produce muscle fibers: they will allow us to better understand the fundamental mechanisms of proliferation and differentiation of healthy and pathological cells, and to develop pre-clinical approaches.
Regenerative capacity is limited in degenerative muscle diseases due to intrinsic stem cell defects and a hostile microenvironment. Oxidative stress is recognized as an deleterious factor in various pathologies and could limit the effectiveness of pharmacological and cellular therapeutic approaches (Lawler, 2011). A number of clinical trials have been conducted to assess the effectiveness of an antioxidant strategy in these pathologies. Unfortunately, most of these clinical trials yielded negative results (Steinhubl, 2008). Nevertheless, I participated in a clinical trial which showed that nutritional supplementation with antioxidants had beneficial effects on certain functional deficits in patients with FacioScapuloHumeral Dystrophy (FSHD) (Passerieux et al. , 2015). I also participated in a number of works on muscle stem cells from patients with FSHD in collaboration with the team of Dr. Yegor Vassetzky, Institut Gustave Roussy, Paris (Bou Saada et al., 2016; Dib et al ., 2016; Dmitriev et al., 2014) in order to characterize the oxidative stress of these cells and the therapeutic efficacy of antioxidants.
We have used muscle stem cells to identify and characterize molecules and their target genes that control muscle stem cell viability. We have shown that aldehyde dehydrogenase (ALDH) activity, a family of enzymes with antioxidant activity, is elevated in a subpopulation of human myoblasts. This activity was associated with an increase in cell survival, ex vivo, and in vivo (Jean et al., 2011). Some ALDHs also catalyze the oxidation of vitamin A to retinoic acid (RA), which binds and activates nuclear retinoic acid receptors. We hypothesized that all or part of the ALDH activity could be due to the production of RA. We have shown that RA improves the viability of myoblasts by increasing the expression of GPX3, an enzyme with antioxidant activity (El Haddad et al., 2012; El Haddad et al., 2017). Based on this experience, I wanted to identify natural molecules with antioxidant capacity. To determine the active molecule(s) of the plant extracts, we then set up a collaboration with Dr Sylvie Morel from the team of phytochemists "Natural Substances and Chemical Mediations" CEFE CNRS UMR 5175 headed by Pr Sylvie Rapior. This led to the identification of two molecules with strong antioxidant activity, taxodione, from rosemary branches and onopordopicrin extracted from Burdock leaves. Taxodione and onopordopicrin effectively protect skeletal muscle cells from damage induced by oxidative stress. Additionally, taxodione reduced lipid and protein oxidation during postmortem muscle preservation. In conclusion, these molecules could stabilize oxidative stress in various human pathologies but also in certain agri-food areas where oxidative damage leads to undesired alterations (El Khatib et al., 2021; Morel et al., 2019) (patent N° 18305871.8. 2018. “Taxodione for its use for protecting muscle and meat from oxidation” European; patent N° FR2000078. “Use of taxodione as an anti-glycation agent”. France).
We then used human muscle stem cells to select natural molecules with anabolic activities considering their efficacy and toxicity. We showed that a rosemary leaf extract was able to induce human muscle cell hypertrophy. We showed that carnosol, a phenolic diterpene, was the active component responsible for this hypertrophy in young and old skeletal muscle cells by repressing the E3 ubiquitin ligase MurF1 and consequently the degradation of proteins dependent on the ubiquitin-proteasome system. (Morel et al., 2021)(patent N° 18306811.3. “Use of carnosol for increasing muscle protein synthesis” European).

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