The myotubularin–amphiphysin 2 complex in membrane tubulation and centronuclear myopathies

Royer, Barbara; Hnia, Karim; Gavriilidis, Christos; Tronchère, Hélène; Tosch, Valérie; Laporte, Jocelyn

doi:10.1038/embor.2013.119

Cited by 61 publications

(54 citation statements)

References 24 publications

(49 reference statements)

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“…S6). This interpretation also fits with the proposed role of MTM1 and associated protein amphiphysin-2 in membrane tubulation (15) and with the fact that disrupted continuity of Ca 2+ transients was observed in muscle fibers downexpressing amphiphysin 2 (16).…”

Section: Discussionsupporting

confidence: 65%

“…Nevertheless, it remains uncertain whether t-tubule structure disruption occurs as a separate mechanism or is intimately linked to the deficiency of Ca 2+ release. A separate mechanism could rely on the known functional interactions between MTM1, dynamin 2 (DNM2), and amphiphysin 1 (BIN1) that are believed to promote membrane tubulation (15). As recently suggested (20), MTM1 loss of activity may lead to decreased levels of PtdIns(5)P and PtdIns(4,5)P 2 .…”

Section: Discussionmentioning

confidence: 99%

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Phosphatidylinositol 3-kinase inhibition restores Ca ²⁺ release defects and prolongs survival in myotubularin-deficient mice

Kutchukian

Scrudato

Tourneur

et al. 2016

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

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Mutations in the gene encoding the phosphoinositide 3-phosphatase myotubularin (MTM1) are responsible for a pediatric disease of skeletal muscle named myotubular myopathy (XLMTM). Muscle fibers from MTM1-deficient mice present defects in excitation-contraction (EC) coupling likely responsible for the disease-associated fatal muscle weakness. However, the mechanism leading to EC coupling failure remains unclear. During normal skeletal muscle EC coupling, transverse (t) tubule depolarization triggers sarcoplasmic reticulum (SR) Ca 2+ release through ryanodine receptor channels gated by conformational coupling with the t-tubule voltage-sensing dihydropyridine receptors. We report that MTM1 deficiency is associated with a 60% depression of global SR Ca 2+ release over the full range of voltage sensitivity of EC coupling. SR Ca 2+ release in the diseased fibers is also slower than in normal fibers, or delayed following voltage activation, consistent with the contribution of Ca 2+ -gated ryanodine receptors to EC coupling. In addition, we found that SR Ca 2+ release is spatially heterogeneous within myotubularin-deficient muscle fibers, with focally defective areas recapitulating the global alterations. Importantly, we found that pharmacological inhibition of phosphatidylinositol 3-kinase (PtdIns 3-kinase) activity rescues the Ca 2+ release defects in isolated muscle fibers and increases the lifespan and mobility of XLMTM mice, providing proof of concept for the use of PtdIns 3-kinase inhibitors in myotubular myopathy and suggesting that unbalanced PtdIns 3-kinase activity plays a critical role in the pathological process.skeletal muscle | excitation-contraction coupling | ryanodine receptor | sarcoplasmic reticulum Ca 2+ release | myotubularin I mpaired skeletal muscle excitation-contraction (EC) coupling is believed to be a main cause of the severe muscle weakness associated with myotubular myopathy (1). EC coupling operates through interactions between the voltage-sensing CAV1.1 Ca 2+ channel (also known as the dihydropyridine receptor) in the transverse (t) tubule membrane and the type 1 ryanodine receptor (RYR1) Ca 2+ release channel in the junctional sarcoplasmic reticulum (SR) membrane: Opening of RYR1 channels under the control of the CAV1.1 voltage-sensing activity is responsible for the Ca 2+ flux that raises cytosolic Ca 2+ to trigger contraction (2, 3). Myotubular myopathy is due to genetic deficiency in the phosphoinositide (phosphatidylinositol, PtdInsP) phosphatase MTM1, which dephosphorylates PtdIns(3,5)P 2 and PtdIns(3)P at the D3 position of the inositol ring (4, 5). How MTM1 deficiency is responsible for defective EC coupling remains unclear, and this issue is highly relevant to understanding the mechanisms of the disease but also to gaining insights into the interactions between phosphoinositides and Ca 2+ signaling in muscle (see ref. 6). The Mtm1-KO mouse model reproduces the main symptomatic features of the human disease: Mutant mice develop a progressive myopathy that starts at about 3-4 wk of ...

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 3-kinase inhibition restores Ca ²⁺ release defects and prolongs survival in myotubularin-deficient mice

Kutchukian

Scrudato

Tourneur

et al. 2016

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

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“…Altogether, these results indicate that both MTM1 and BIN1 act upstream of DNM2. Indeed, BIN1 can bind to MTM1 and also to DNM2, and BIN1-CNM mutations interfere with its ability to interact with MTM1 and DNM2 (7,42), indicating the importance of this pathway in muscle and disease. Moreover, DNM2 downregulation becomes a potential strategy to rescue several myopathy forms (linked to either MTM1 or BIN1 mutations).…”

Section: Rt-pcr and Isoform Detectionmentioning

confidence: 99%

Amphiphysin (BIN1) negatively regulates dynamin 2 for normal muscle maturation

Cowling¹,

Prokić²,

Tasfaout³

et al. 2017

Journal of Clinical Investigation

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123

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“…homeostasis. BIN1 is a binding partner of MTM1 and MTM1 promotes BIN1-mediated membrane tubulation (Royer et al 2013) which underlies a possible common pathological mechanism in the two corresponding centronuclear myopathies. The importance of MTM1 and BIN1 in structure maintenance and EC coupling function was confirmed in zebrafish models (Dowling et al 2009;Smith et al 2014).…”

Section: Newcomersmentioning

confidence: 99%

Phosphoinositides in Ca2+ signaling and excitation–contraction coupling in skeletal muscle: an old player and newcomers

Csernoch

Jacquemond

2015

J Muscle Res Cell Motil

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Since the postulate, 30 years ago, that phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2) as the precursor of inositol 1,4,5-trisphosphate (Ins(1,4,5)P 3) would be critical for skeletal muscle excitation-contraction (EC) coupling, the issue of whether phosphoinositides (PtdInsPs) may have something to do with Ca(2+) signaling in muscle raised limited interest, if any. In recent years however, the PtdInsP world has expanded considerably with new functions for PtdIns(4,5)P 2 but also with functions for the other members of the PtdInsP family. In this context, the discovery that genetic deficiency in a PtdInsP phosphatase has dramatic consequences on Ca(2+) homeostasis in skeletal muscle came unanticipated and opened up new perspectives in regards to how PtdInsPs modulate muscle Ca(2+) signaling under normal and disease conditions. This review intends to make an update of the established, the questioned, and the unknown regarding the role of PtdInsPs in skeletal muscle Ca(2+) homeostasis and EC coupling, with very specific emphasis given to Ca(2+) signals in differentiated skeletal muscle fibers.

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The myotubularin–amphiphysin 2 complex in membrane tubulation and centronuclear myopathies

Cited by 61 publications

References 24 publications

Phosphatidylinositol 3-kinase inhibition restores Ca ²⁺ release defects and prolongs survival in myotubularin-deficient mice

Phosphatidylinositol 3-kinase inhibition restores Ca ²⁺ release defects and prolongs survival in myotubularin-deficient mice

Amphiphysin (BIN1) negatively regulates dynamin 2 for normal muscle maturation

Phosphoinositides in Ca2+ signaling and excitation–contraction coupling in skeletal muscle: an old player and newcomers

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The myotubularin–amphiphysin 2 complex in membrane tubulation and centronuclear myopathies

Cited by 61 publications

References 24 publications

Phosphatidylinositol 3-kinase inhibition restores Ca 2+ release defects and prolongs survival in myotubularin-deficient mice

Phosphatidylinositol 3-kinase inhibition restores Ca 2+ release defects and prolongs survival in myotubularin-deficient mice

Amphiphysin (BIN1) negatively regulates dynamin 2 for normal muscle maturation

Phosphoinositides in Ca2+ signaling and excitation–contraction coupling in skeletal muscle: an old player and newcomers

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Product

Resources

About

Phosphatidylinositol 3-kinase inhibition restores Ca ²⁺ release defects and prolongs survival in myotubularin-deficient mice

Phosphatidylinositol 3-kinase inhibition restores Ca ²⁺ release defects and prolongs survival in myotubularin-deficient mice