Myotubularin controls desmin intermediate filament architecture and mitochondrial dynamics in human and mouse skeletal muscle
Karim Hnia, … , Jean Louis Mandel, Jocelyn Laporte
Karim Hnia, … , Jean Louis Mandel, Jocelyn Laporte
Published December 6, 2010
Citation Information: J Clin Invest. 2011;121(1):70-85. https://doi.org/10.1172/JCI44021.
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Myotubularin controls desmin intermediate filament architecture and mitochondrial dynamics in human and mouse skeletal muscle

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.

Authors

Karim Hnia, Helene Tronchère, Kinga K. Tomczak, Leonela Amoasii, Patrick Schultz, Alan H. Beggs, Bernard Payrastre, Jean Louis Mandel, Jocelyn Laporte

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Figure 2

Dissection of the MTM1-desmin interaction.

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Dissection of the MTM1-desmin interaction. (A) Schematic of the MTM1 pro...
(A) Schematic of the MTM1 protein domains. Pulldown of GST-fusion domains of MTM1 with extracts from COS-1 cells overexpressing desmin. Desmin interacted with the ΔGRAM domain. (B) Prediction model for MTM1 based on the MTMR2 crystallographic model using PyMol software. The outlined region (shown in detail at right) represents the potential domain for interaction with desmin, composed of 4 independent loops with indicated residues exposed to outside space. aas labeled in red are implicated in desmin binding; histograms represent the relative binding of listed MTM1 constructs (deletion and aa mutation). (C) Prediction model for MTM1, showing loops implicated in desmin interaction based on peptide mapping and competition experiments (Supplemental Figure 3, D and E). (D) Desmin binding domain. Schematic representation of desmin domains. Dashed lines outline the common region between Y2H clones. The region of desmin implicated in MTM1 binding was determined by peptide mapping experiments. Quantitation of desmin peptides’ affinity for MTM1 compared with a non-desmin peptide (CTR). Data were correlated from 3 independent experiments, and statistical analysis of the difference in intensities between positive peptides was set at *P ≤ 0.05.