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PMID:21135508

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Citation

Hnia, K, Tronchère, H, Tomczak, KK, Amoasii, L, Schultz, P, Beggs, AH, Payrastre, B, Mandel, JL and Laporte, J (2011) Myotubularin controls desmin intermediate filament architecture and mitochondrial dynamics in human and mouse skeletal muscle. J. Clin. Invest. 121:70-85

Abstract

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.

Links

PubMed PMC3007152 Online version:10.1172/JCI44021

Keywords

Animals; Cell Line; Desmin/genetics; Desmin/physiology; Humans; Intermediate Filaments/physiology; Intermediate Filaments/ultrastructure; Mice; Mice, Knockout; Microscopy, Electron, Transmission; Mitochondria, Muscle/physiology; Mitochondria, Muscle/ultrastructure; Models, Molecular; Muscle, Skeletal/physiology; Muscle, Skeletal/ultrastructure; Mutation; Myopathies, Structural, Congenital/genetics; Myopathies, Structural, Congenital/physiopathology; Protein Interaction Domains and Motifs; Protein Tyrosine Phosphatases, Non-Receptor/deficiency; Protein Tyrosine Phosphatases, Non-Receptor/genetics; Protein Tyrosine Phosphatases, Non-Receptor/physiology; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:DESM

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P17661

F

Seeded From UniProt

complete

HUMAN:DESM

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13496

F

Seeded From UniProt

complete

MOUSE:DESM

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13496

F

Seeded From UniProt

complete

MOUSE:DESM

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Z2C5

F

Seeded From UniProt

complete

HUMAN:MTM1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P17661

F

Seeded From UniProt

complete

HUMAN:MTM1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P31001

F

Seeded From UniProt

complete

MOUSE:MTM1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P31001

F

Seeded From UniProt

complete

HUMAN:MTM1

enables

GO:0019215: intermediate filament binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MTM1

involved_in

GO:0070584: mitochondrion morphogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MTM1

involved_in

GO:0048311: mitochondrion distribution

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MTM1

involved_in

GO:0045109: intermediate filament organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MTM1

involved_in

GO:0048311: mitochondrion distribution

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MTM1

involved_in

GO:0070584: mitochondrion morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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