The metabolic signature of muscle stem cells during acute and chronic skeletal muscle regeneration

Although skeletal muscle metabolism is generally considered at the muscle fiber scale, it is now clear that metabolism also plays an important role in the functioning of the muscle stem cell (MuSC). In particular, the key cellular functions of metabolism (i.e. energy production, macromolecule synthesis, elimination of degraded macromolecules/organelles, substrate production and extraction, and renewal of cell components) can modulate the steps of the MuSC fate: quiescence, activation, proliferation/expansion, differentiation, fusion, and self-renewal/dormancy. To address “metabolic stemness” (i.e. distinct metabolic characteristics of MuSC states), we propose a metabolomic approach to perform an in-depth analysis of the metabolism of stem cells. Metabolomics enables the characterization of endogenous small molecules revealing connections between different pathways that actually operate within a living cell. Whereas significant effort has focused on using synthetic small molecules to control MuSC function, our metabolomic study will identify novel skeletal muscle-specific metabolites (i.e. endogenous molecules) that modulate MuSC fate and skeletal muscle homeostasis.

Investigate the role of AMPK and the AMPK-related kinases in MuSC homeostasis

AMPK and AMPK-related kinases are key metabolic sensors, and central coordinators of cellular metabolism. Therefore, we aim to decipher their role in the regulation of MuSC fate and adult myogenesis. In particular, we aim at understand their role in the maintenance of the MuSC pool through the regulation of cell division and self-renewal.

AMPK signaling pathway as a novel therapeutic for Myotonic Dystrophy Type 1 (DM1)

We will decipher the role of AMPK and NUAK1-dependent pathways in the splicing deregulation associated with DM1. In addition, our goal is to establish the potential of AMPK and/or NUAK1 activation in managing DM1 symptoms, in particular skeletal muscle atrophy and mitochondrial dysfunction, and to provide leads towards novel therapeutic strategies for DM1.

SELECTED PUBLICATIONS

• Annexin A1 drives macrophage skewing to accelerate muscle regeneration through AMPK activation. McArthur S, Juban G, Gobbetti T, Desgeorges T, Theret M, Gondin J, Toller-Kawahisa JE, Reutelingsperger CP, Chazaud B, Perretti M#, Mounier R#. J Clin Invest, 2020 Mar 2;130(3):1156-1167
• Macrophage-derived superoxide production and antioxidant response following skeletal muscle injury. Le Moal E, Juban G, Bernard AS, Varga T, Policar C, Chazaud B, Mounier R. Free Radic Biol Med, 2018, 20;120:33-40
• AMPKa1-LDH pathway regulates muscle stem cell self-renewal by controlling metabolic homeostasis. Theret M, Gsaier L, Schaffer B, Juban G, Ben Larbi S, Weiss-Gayet M, Bultot L, Collodet C, Foretz M, Desplanches D, Sanz P, Zang Z, Yang L, Vial G, Viollet B, Sakamoto K, Brunet A, Chazaud B, Mounier R. EMBO J, 2017, 36:1946-1962
• Macrophage PPARγ, a Lipid Activated Transcription Factor Controls the Growth Factor GDF3 and Skeletal Muscle Regeneration. Varga T#, Mounier R#, Patsalos A, Gogolák P, Peloquin M, Horvath A, Pap A, Daniel B, Nagy G, Pintye E, Póliska S, Cuvellier S, Larbi SB, Sansbury BE, Spite M, Brown CW, Chazaud B, Nagy L. Immunity, 2016, 45:1038-1051
• Myeloid HIFs are dispensable for resolution of inflammation during skeletal muscle regeneration. Gondin J, Theret M, Duhamel G, Pegan K, Mathieu JR, Peyssonnaux C, Cuvellier S, Latroche C, Chazaud B, Bendahan D, Mounier R. J Immunol, 2015, 194:3389-3399
• AMPKalpha1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration. Mounier R#, Theret M#, Arnold L, Cuvellier S, Bultot L, Goransson O, Sanz N, Ferry A, Sakamoto K, Foretz M, Viollet B, Chazaud B. Cell Metab, 2013, 18:251-264

FUNDING

• Actions Marie Skłodowska-Curie
• Agence Nationale de la Recherche
• Association Française contre les Myopathies
• CNRS
• Fondation pour la Recherche Médicale
• INSERM
• Programme France Excellence