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.

A phosphoinositide conversion mechanism for exit from endosomes

“…Moreover, PIKfyve depletion mimicked the peripheral accumulation of TfR-endosomes, although less prominently than the loss of MTM1, while exocytosis was not affected (Figure 26a-c). Thus, we conclude that exit from endosomes en route to late endosomes/ lysosomes functions as a save guard in MTM1-depleted cells to avoid accumulation of early endosomal PI(3)P. Despite the fact that PI(3,5)P 2 could be an additional substrate for MTM1 3-phosphatase activity in vitro (Cao, Backer et al 2008;Hnia, Tronchere et al 2011), lowering endosomal PI(3,5)P 2 levels by co-depletion of PIKfyve did not affect phenotypic changes observed upon loss of MTM1. Thus, endosomal defects caused by loss of MTM1 are primarily due to elevated PI(3)P, but not PI(3,5)P 2 levels.…”

“…Taken together, these data indicates that balancing PI(3)P-level is essential for endomembranes traffic. (Hnia, Tronchere et al 2011). Although the primary and most striking phenotype of MTM1-loss-of-function affects muscle fibers, patients with a milder form of XLCNM carrying MTM1 missense mutations develop additional symptoms such as liver dysfunction (Herman, Finegold et al 1999).…”

“…In addition to these defects (see Figure 40, (1)), the pathophysiology of XLCNM patients include: (2) mitochondrial redistribution and dysfunction; (3) defects in myofibrillar force generation; (4) atrophy; and (5) defects in autophagy induction and autophagic flux ( Figure 40) (Ravenscroft, Laing et al 2015 (Hnia, Tronchere et al 2011). …”

Myotubularine et desmine

“…La seconde voie semble indé-pendante de la desmine et son méca-nisme reste encore à élucider. En conclusion, cette étude a identifié un partenariat inattendu entre deux protéines impliquées dans des pathologies musculaires différentes [7]. Ce lien l'effet de MTM1 sur les filaments de desmine.…”

“…La desmine : un nouveau partenaire musculaire de MTM1 Par une approche de double hybride dans la levure, nous avons identifié la desmine comme un ligand potentiel de MTM1 [7]. Cette protéine appartient à la famille des filaments intermédiaires.…”