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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Research Article Muscle biology Article has an altmetric score of 7

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 9

Involvement of MTM1 in mitochondrial function and homeostasis in muscle.

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Involvement of MTM1 in mitochondrial function and homeostasis in muscle....
(A) Decreased cytochrome oxidase activity in Mtm1-KD C2C12 and XLCNM patient myoblasts and myotubes. Cell lines from 3 XLCNM patients were assayed. 3 independent experiments were analyzed. *P ≤ 0.05. (B) ATP content of total muscle homogenates from WT and Mtm1-KO mice. *P ≤ 0.05. (C) Mitochondria freshly isolated from mouse muscle were used to measure Ca2+-induced MPT. Changes observed during the 18-minute period are shown for WT and Mtm1-KO mitochondria in the presence and absence of Ca2+. (D) Cytochrome c release was monitored from freshly isolated mitochondria from WT and Mtm1-KO muscles. Mitochondria were incubated with or without Ca2+, followed by analysis of cytochrome c released to the supernatant. (B–D) Data were correlated from 2 independent experiments (3 mice per group; 2 tibialis anterior muscles per mouse). (E) Decreased MTM1 levels did not enhance apoptotic events. TUNEL assay was used to determine the apoptotic rate of control and Mtm1-KD cells. FACS analysis showed no significant difference in the profile of control and KD samples. Data are representative of 3 independent experiments. (F) Diagram illustrating IF-binding proteins and their associated diseases together with potential connection to mitochondrial dynamics and function. EB-MD, epidermolysis bullosa with muscular dystrophy; Mb, membrane.