Myotubularin controls desmin intermediate filament architecture and mitochondrial dynamics in human and mouse skeletal muscle.
Muscle contraction relies on a highly organized intracellular network of membrane organelles and cytoskeleton proteins. Among the latter are the intermediate filaments (IFs), a large family of proteins mutated in more than 30 human diseases. For example, mutations in the DES gene, which encodes the IF desmin, lead to desmin-related myopathy and cardiomyopathy. Here, we demonstrate that myotubularin (MTM1), which is mutated in individuals with X-linked centronuclear myopathy (XLCNM; also known as myotubular myopathy), is a desmin-binding protein and provide evidence for direct regulation of desmin by MTM1 in vitro and in vivo. XLCNM-causing mutations in MTM1 disrupted the MTM1-desmin complex, resulting in abnormal IF assembly and architecture in muscle cells and both mouse and human skeletal muscles. Adeno-associated virus-mediated ectopic expression of WT MTM1 in Mtm1-KO muscle reestablished normal desmin expression and localization. In addition, decreased MTM1 expression and XLCNM-causing mutations induced abnormal mitochondrial positioning, shape, dynamics, and function. We therefore conclude that MTM1 is a major regulator of both the desmin cytoskeleton and mitochondria homeostasis, specifically in skeletal muscle. Defects in IF stabilization and mitochondrial dynamics appear as common physiopathological features of centronuclear myopathies and desmin-related myopathies.
Department of Neurobiology and Genetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Karim
K
Hnia
Helene
H
Tronchère
Kinga K
KK
Tomczak
Leonela
L
Amoasii
Patrick
P
Schultz
Alan H
AH
Beggs
Bernard
B
Payrastre
Jean Louis
JL
Mandel
Jocelyn
J
Laporte
D000818:Animals; D002460:Cell Line; D003893:Desmin / Q000235:genetics / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007382:Intermediate Filaments / Q000502:physiology / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008931:Mitochondria, Muscle / Q000502:physiology / Q000648:ultrastructure; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000502:physiology* / Q000648:ultrastructure; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics / Q000503:physiopathology; D054730:Protein Interaction Domains and Motifs; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D003893:Desmin; D011993:Recombinant Fusion Proteins; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin