Familial “myotubular” myopathy

Wijngaarden, G.K. van; Fleury, P; Bethlem, J.; Meijer, A. E. F. H.

doi:10.1212/wnl.19.9.901

Cited by 122 publications

(54 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Loss-of-function myotubularin mutations are causative for X-linked recessive myotubular myopathy (1,2). XLMTM is characterized by skeletal muscle fibers with numerous centrally located nuclei that are markedly atrophic/hypotrophic.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Myotubularin Regulates Akt-dependent Survival Signaling via Phosphatidylinositol 3-Phosphate

Razidlo¹,

Katafiasz²,

Taylor

2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Myotubularin is a 3-phosphoinositide phosphatase that is mutated in X-linked myotubular myopathy, a severe neonatal disorder in which skeletal muscle development and/or regeneration is impaired. In this report we provide evidence that siRNA-mediated silencing of myotubularin expression markedly inhibits growth factor-stimulated Akt phosphorylation, leading to activation of caspase-dependent pro-apoptotic signaling in HeLa cells and primary human skeletal muscle myotubes. Myotubularin silencing also inhibits Akt-dependent signaling through the mammalian target of rapamycin complex 1 as assessed by p70 S6-kinase and 4E-BP1 phosphorylation. Similarly, phosphorylation of FoxO transcription factors is also significantly reduced in myotubularin-deficient cells. Our data further suggest that inhibition of Akt activation and downstream survival signaling in myotubularin-deficient cells is caused by accumulation of the MTMR substrate lipid phosphatidylinositol 3-phosphate generated from the type II phosphatidylinositol 3-kinase PIK3C2B. Our findings are significant because they suggest that myotubularin regulates Akt activation via a cellular pool of phosphatidylinositol 3-phosphate that is distinct from that generated by the type III phosphatidylinositol 3-kinase hVps34. Because impaired Akt signaling has been tightly linked to skeletal muscle atrophy, we hypothesize that loss of Akt-dependent growth/survival cues due to impaired myotubularin function may be a critical factor underlying the severe skeletal muscle atrophy characteristic of muscle fibers in patients with X-linked myotubular myopathy.Myotubularin is the archetypical member of a family of phosphoinositide 3-phosphatases. Mutations in the myotubularin gene are causative for X-linked recessive myotubular myopathy (XLMTM), 4 also known as "centronuclear myopathy." XLMTM is a severe neonatal disorder in which the maturation and/or regeneration of skeletal muscle fibers is compromised (1, 2). Myofibers from affected individuals display abnormal centrally located nuclei and are severely atrophic. Mice in which the myotubularin gene has been deleted exhibit a skeletal muscle phenotype consistent with that of XLMTM disease. Like XLMTM patients, early stages of myogenesis in these mice appear to occur normally, and it has been suggested that skeletal muscle maintenance or regeneration is affected rather than early myogenic differentiation (3). Mutations in two other MTMR family proteins, MTMR2 and MTMR13, are causative for the demyelinating peripheral neuropathy type 4B Charcot-Marie-Tooth disease (4 -6).The myotubularin-related protein (MTMR) family consists of 14 proteins including 8 catalytically active lipid phosphatases and 6 forms that are inactive due to germ-line substitutions of essential catalytic residues (7). Active MTMRs specifically remove the 3-phosphate moiety from phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P 2 ), generating phosphatidylinositol (PI) and phosphatidylinositol 5-phosphate (PI(5)P), respectively (...

show abstract

Section: Discussionmentioning

confidence: 99%

“…XLMTM is a severe neonatal disorder in which the maturation and/or regeneration of skeletal muscle fibers is compromised (1,2). Myofibers from affected individuals display abnormal centrally located nuclei and are severely atrophic.…”

mentioning

confidence: 99%

Myotubularin Regulates Akt-dependent Survival Signaling via Phosphatidylinositol 3-Phosphate

Razidlo¹,

Katafiasz²,

Taylor

2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The founding member of the family of myotubularin-related proteins is the human gene MTM1, which is mutated in X-linked myotubular myopathy, a severe congenital disorder that is characterized by small rounded muscle fibers with varying percentages of centrally located nuclei that resemble fetal myotubes [580][581][582][583][584][585][586][587]. Owing to the fact that it contains a number of conserved motifs, then known as hallmarks for dual specificity protein tyrosine phosphatases, Mtm1 has long been thought to serve as a protein phosphatase [581,588].…”

Section: Myotubularin Ortholog (Ymr1)mentioning

confidence: 99%

Synthesis and function of membrane phosphoinositides in budding yeast, Saccharomyces cerevisiae

Strahl

Thorner

2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

274

315

View full text Add to dashboard Cite

It is now well appreciated that derivatives of phosphatidylinositol (PtdIns) are key regulators of many cellular processes in eukaryotes. Of particular interest are phosphoinositides (mono-and polyphosphorylated adducts to the inositol ring in PtdIns), which are located at the cytoplasmic face of cellular membranes. Phosphoinositides serve both a structural and a signaling role via their recruitment of proteins that contain phosphoinositide-binding domains. Phosphoinositides also have a role as precursors of several types of second messengers for certain intracellular signaling pathways. Realization of the importance of phosphoinositides has brought increased attention to characterization of the enzymes that regulate their synthesis, interconversion, and turnover. Here we review the current state of our knowledge about the properties and regulation of the ATP-dependent lipid kinases responsible for synthesis of phosphoinositides and also the additional temporal and spatial controls exerted by the phosphatases and a phospholipase that act on phosphoinositides in yeast.

show abstract

“…Histopathological studies of the skeletal muscle in these patients reveal the presence of small rounded muscle fibers that contain centrally located nuclei surrounded by a halo devoid of myofibrils where mitochondria accumulate (5,6). These fibers resemble fetal myotubes, and it was suggested that the disease may result from an arrest in the normal development of muscle fibers at the myotubular stage (7,8). The gene responsible for XLMTM, MTM1, was isolated by positional cloning (9).…”

mentioning

confidence: 99%

The lipid phosphatase myotubularin is essential for skeletal muscle maintenance but not for myogenesis in mice

Buj‐Bello

Laugel

Messaddeq

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

197

207

View full text Add to dashboard Cite

Myotubularin is a ubiquitously expressed phosphatase that acts on phosphatidylinositol 3-monophosphate [PI(3)P], a lipid implicated in intracellular vesicle trafficking and autophagy. It is encoded by the MTM1 gene, which is mutated in X-linked myotubular myopathy (XLMTM), a muscular disorder characterized by generalized hypotonia and muscle weakness at birth leading to early death of most affected males. The disease was proposed to result from an arrest in myogenesis, as the skeletal muscle from patients contains hypotrophic fibers with centrally located nuclei that resemble fetal myotubes. To understand the physiopathological mechanism of XLMTM, we have generated mice lacking myotubularin by homologous recombination. These mice are viable, but their lifespan is severely reduced. They develop a generalized and progressive myopathy starting at around 4 weeks of age, with amyotrophy and accumulation of central nuclei in skeletal muscle fibers leading to death at 6 -14 weeks. Contrary to expectations, we show that muscle differentiation in knockout mice occurs normally. We provide evidence that fibers with centralized myonuclei originate mainly from a structural maintenance defect affecting myotubularin-deficient muscle rather than a regenerative process. In addition, we demonstrate, through a conditional gene-targeting approach, that skeletal muscle is the primary target of murine XLMTM pathology. These mutant mice represent animal models for the human disease and will be a valuable tool for understanding the physiological role of myotubularin.

show abstract

Familial “myotubular” myopathy

Cited by 122 publications

References 0 publications

Myotubularin Regulates Akt-dependent Survival Signaling via Phosphatidylinositol 3-Phosphate

Myotubularin Regulates Akt-dependent Survival Signaling via Phosphatidylinositol 3-Phosphate

Synthesis and function of membrane phosphoinositides in budding yeast, Saccharomyces cerevisiae

The lipid phosphatase myotubularin is essential for skeletal muscle maintenance but not for myogenesis in mice

Contact Info

Product

Resources

About