Physiopathologie et traitements des myopathies myotubulaires et centronucléaires

Physiopathologie et traitements des myopathies myotubulaires et centronucléaires



Centronuclear and myotubular myopathies (CNM) are rare and severe genetic myopathies with a strong burden on patients, their families and our healthcare system. They associate muscle weakness and hypotonia, respiratory distress and abnormal organelles positioning in myofibers. We previously identified 3 main genes mutated in CNM, all encoding proteins that regulate membrane and cytoskeleton dynamics: the phosphoinositides phosphatase myotubularin (MTM1), the membrane remodeling amphiphysin 2 (BIN1), and the membrane fissioning GTPase dynamin 2 (DNM2).

We now aim to

  1. decipher the pathological mechanisms
  2. validate therapeutic proof-of-concepts.

Projets en cours

Elucidating the intracellular organization and homeostasis of skeletal muscle

Muscle fibers can contract, are syncytia from the fusion of myoblasts, can have several hundred nuclei, measure up to 30cm in human, and account for nearly half of the dried body weight. They have specific intracellular organization and specialized membrane structures. I and my team identified the Myotubularin family (Laporte et al. 1998) and showed these proteins act mainly as phosphoinositides phosphatases regulating autophagy (Blondeau et al. 2002; Vergne et al. 2009), misfolded proteins degradation (Gavriilidis et al. 2018), reticulum remodelling (Amoasii et al. 2013) and phosphoinositides conversion in recycling (Ketel et al. 2016). Several members are mutated in neuromuscular diseases (MTM1, MTMR2, MTMR5, MTMR13). We also revealed how different proteins mutated in centronuclear myopathies (myotubularin-MTM1, and amphiphysin-BIN1) control focal adhesion (Lionello et al. 2019) and nuclear (D’Alessandro et al. 2015) or mitochondria (Hnia et al. 2011) positioning through the interaction with nesprin and desmin, two other proteins mutated in myopathies, linking several myopathies into a common cellular pathway.

  • Amoasii et al. Myotubularin and PtdIns3P remodel the sarcoplasmic reticulum in muscle in vivo. J Cell Sci. 2013 Apr 15;126(Pt 8):1806-19.
  • Blondeau et al. Myotubularin, a phosphatase deficient in myotubular myopathy, acts on phosphatidylinositol 3-kinase and phosphatidylinositol 3-phosphate pathway. Hum Mol Genet. 2000 Sep 22;9(15):2223-9.
  • D’Alessandro et al. Amphiphysin 2 Orchestrates Nucleus Positioning and Shape by Linking the Nuclear Envelope to the Actin and Microtubule Cytoskeleton. Dev Cell 2015 Oct 26;35(2):186-198.
  • Gavriilidis et al. The MTM1-UBQLN2-HSP complex mediates degradation of misfolded intermediate filaments in skeletal muscle. Nat Cell Biol. 2018 Jan 22.
  • Hnia et al. Myotubularin controls desmin intermediate filament architecture and mitochondrial dynamics in human and mouse skeletal muscle. J Clin Invest. 2011 Jan 4;121(1):70-85.
  • Ketel et al. A phosphoinositide conversion mechanism for exit from endosomes. Nature 2016 Jan 21;529(7586):408-12.
  • Laporte et al. Characterization of the myotubularin dual specificity phosphatase gene family from yeast to human. Hum Mol Genet. 1998 Oct;7(11):1703-12.
  • Vergne et al. Control of autophagy by phosphoinositides 3-phosphatase Jumpy. EMBO J. 2009 Aug 5;28(15):2244-58.

Deciphering the pathophysiology of congenital myopathies

To decipher the pathological mechanisms leading to several congenital myopathies, we have characterized 14 novel murine models and identified 3 spontaneous canine models (Beggs et al. 2010; Bohm et al. 2013). We found centronuclear myopathies are linked to defects of organelle positioning and of the triads, the membrane compartment regulating excitation-contraction coupling (AlQusairi et al. 2009; Toussaint et al. 2011). In tubular aggregate myopathies, we discovered that mutations in several components of the store-operated calcium entry (SOCE) pathway regulating calcium homeostasis lead to constitutive activated SOCE and higher calcium entry (Bohm et al. 2013).

  • Al-Qusairi et al. Defective excitation-contraction coupling in muscle fibres lacking myotubularin phosphoinositide phosphatase. Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18763-8.
  • Beggs A et al. MTM1 Mutation Associated with X-Linked Myotubular Myopathy in Labrador Retrievers. Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14697-702.
  • Böhm et al. Altered Splicing of the BIN1 Muscle-Specific Exon in Humans and Dogs with Highly progressive Centronuclear Myopathy. PLoS Genet. 2013 Jun;9(6):e1003430.
  • Böhm et al. Constitutive activation of the calcium sensor STIM1 causes tubular aggregate myopathy. Am J Hum Genet, 2013 Feb 7;92(2):271-8.
  • Toussaint et al. Defects in Amphiphysin 2 (BIN1) and triads in several forms of centronuclear myopathies. Acta Neuropathol. 2011 Feb; 121(2):253-266.

Validation of therapeutic proof-of-concept for congenital myopathies

Most myopathies have no therapy. We identified 5 therapeutic targets and 1 potent drug. Using faithful cellular and animal models and the generated knowledge on the pathomechanisms, we deciphered which functions of myotubularin-MTM1 is necessary for rescuing a mouse model for myotubular myopathy through gene therapy (Amoasii et al. 2012) and showed expression of a close MTM1 homolog, MTMR2, can also rescue the disease (Raess et al. 2017). We validated the proof-of-concept that upregulation of BIN1 encoding amphiphysin 2 can prevent the development of myotubular myopathy due to MTM1 mutations (Lionello et al., 2019). Similarly, inhibition of the kinase activity of PI3K C2beta can also rescue this disease in mice (submitted). We also found tamoxifen, a drug used for breast cancer treatment, ameliorates myotubular myopathy (Gayi et al. 2018). We showed that downregulation of dynamin-DNM2 can prevent and revert myotubular myopathy in mammals through genetic cross, oligonucleotide-mediated or short hairpin RNA interference (Cowling et al. 2014; Tasfaout et al. 2017, 2018) and can be applied to several forms of centronuclear myopathies (Cowling et al. 2017; Buono et al. 2018). This last finding allowed the creation of the biotech company Dynacure end 2016 (, aiming to treat different rare diseases.

  • Amoasii et al. Phosphatase-dead Myotubularin Ameliorates X-linked Centronuclear Myopathy Phenotypes in mice. PLoS Genet. 2012 Oct;8(10):e1002965.
  • Cowling et al. Reducing dynamin 2 expression rescues X-linked Centronuclear Myopathy. J Clin Invest. 2014 Mar 3;124(3):1350-63.
  • Cowling et al. Amphiphysin (BIN1) negatively regulates dynamin 2 for normal muscle maturation. J Clin Invest. 2017 Nov 13. pii: 90542.
  • Gayi et al. Tamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy. Nat Commun. 2018 Nov 19;9(1):4848.
  • Lionello et al. Amphiphysin 2 (BIN1) modulation rescues MTM1 centronuclear myopathy and prevents focal adhesion defects. Sci Transl Med. 2019 Mar 20;11(484).
  • Raess et al. Expression of the neuropathy-associated MTMR2 gene rescues MTM1-associated myopathy. Hum Mol Genet. 2017 Oct 1;26(19):3736-3748.
  • Tasfaout et al. Antisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice. Nat Commun. 2017 Jun 7;8:15661.














Téléthon : des recherches fondamentales au développement d'approches thérapeutiques

A l'occasion de la 36è édition du Téléthon, les scientifiques Jocelyn Laporte, Johann Böhm et Delphine Duteil ont présenté leurs projets de recherches…

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