Structural insights into the centronuclear myopathy-associated functions of BIN1 and dynamin 2

Hohendahl, Annika; Roux, Aurélien; Galli, Valentina

doi:10.1016/j.jsb.2016.06.015

Cited by 32 publications

(35 citation statements)

References 73 publications

(152 reference statements)

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“…) and a proper balance between the tubulation activity of BIN1 and the fission activity of dynamin 2 has been suggested to be critical for t‐tubule maintenance; however, the details of how the three proteins, in association with phosphoinositide metabolism, ensure proper t‐tubule homeostasis/maintenance are far from completely understood and the role of MTM1 in the framework is specifically unclear (Hohendahl et al . ). One other equivocal aspect of this issue is that BIN1 and MTM1 appear to concentrate in the triadic region (Rodriguez et al .…”

Section: Discussionmentioning

confidence: 97%

Impaired excitation–contraction coupling in muscle fibres from the dynamin2^R465W mouse model of centronuclear myopathy

Kutchukian

Szentesi

Allard

et al. 2017

The Journal of Physiology

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Mutations in the gene encoding dynamin 2 (DNM2) are responsible for autosomal dominant centronuclear myopathy (AD-CNM). We studied the functional properties of Ca signalling and excitation-contraction (EC) coupling in muscle fibres isolated from a knock-in (KI) mouse model of the disease, using confocal imaging and the voltage clamp technique. The transverse-tubule network organization appeared to be unaltered in the diseased fibres, although its density was reduced by ∼10% compared to that in control fibres. The density of Ca current through CaV1.1 channels and the rate of voltage-activated sarcoplasmic reticulum Ca release were reduced by ∼60% and 30%, respectively, in KI vs. control fibres. In addition, Ca release in the KI fibres reached its peak value 10-50 ms later than in control ones. Activation of Ca transients along the longitudinal axis of the fibres was more heterogeneous in the KI than in the control fibres, with the difference being exacerbated at intermediate membrane voltages. KI fibres exhibited spontaneous Ca release events that were almost absent from control fibres. Overall, the results of the present study demonstrate that Ca signalling and EC coupling exhibit a number of dysfunctions likely contributing to muscle weakness in DNM2-related AD-CNM.

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Section: Discussionmentioning

confidence: 97%

Impaired excitation–contraction coupling in muscle fibres from the dynamin2^R465W mouse model of centronuclear myopathy

Kutchukian

Szentesi

Allard

et al. 2017

The Journal of Physiology

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“…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 . Because these appear necessary to recruit DNM2 and BIN1 at the plasma membrane to ensure proper membrane tubulation, this would provide an explanation as to how MTM1 phosphatase activity is necessary to maintain t-tubule integrity.…”

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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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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“…CNM-associated Dyn2 mutations are hypermorphic alleles resulting from loss of autoinhibitory regulation, which promotes self-assembly (Faelber, Gao et al, 2013, Hohendahl, Roux et al, 2016. Hyper-assembled Dyn2 is hyperactive, resistant to GTP hydrolysis-induced disassembly, and presents enhanced membrane fission activity (Chin et al, 2015, Kenniston & Lemmon, 2010.…”

Section: Discussionmentioning

confidence: 99%

Dynamin-2 regulates synaptic podosome maturation to facilitate neuromuscular junction development

Lin

Hsieh

Liou

et al. 2020

Preprint

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Neuromuscular junctions (NMJs) govern rapid and efficient neuronal communication with muscle cells, which relies on the proper architecture of specialized postsynaptic compartments. However, the intrinsic mechanism in muscle cells contributing to elaborate NMJ development has been unclear. In this study, we reveal that the GTPase dynamin-2 (Dyn2), bestknown for catalyzing synaptic vesicle endocytosis at the presynaptic membrane, is also involved in postsynaptic morphogenesis. We demonstrate that Dyn2 is enriched in the postsynaptic membrane of muscle cells and is involved in the maturation of neurotransmitter receptor clusters via its actin bundling ability. Dyn2 functions as a molecular girdle to regulate synaptic podosome turnover and promote morphogenesis of the postsynaptic apparatus. In Drosophila NMJs, Dyn2 is required to organize the postsynaptic actin cytoskeleton and to mediate its electrophysiological activities. Mechanistically, the actin binding, self-assembly, GTP hydrolysis ability, and Y597 phosphorylation of Dyn2 all regulate its actin bundling activity. Together, our study uncovers a role for Dyn2 in cytoskeleton remodeling and organization at the postsynaptic membrane of NMJs.

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Structural insights into the centronuclear myopathy-associated functions of BIN1 and dynamin 2

Cited by 32 publications

References 73 publications

Impaired excitation–contraction coupling in muscle fibres from the dynamin2^R465W mouse model of centronuclear myopathy

Impaired excitation–contraction coupling in muscle fibres from the dynamin2^R465W mouse model of centronuclear myopathy

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

Dynamin-2 regulates synaptic podosome maturation to facilitate neuromuscular junction development

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Structural insights into the centronuclear myopathy-associated functions of BIN1 and dynamin 2

Cited by 32 publications

References 73 publications

Impaired excitation–contraction coupling in muscle fibres from the dynamin2R465W mouse model of centronuclear myopathy

Impaired excitation–contraction coupling in muscle fibres from the dynamin2R465W mouse model of centronuclear myopathy

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

Dynamin-2 regulates synaptic podosome maturation to facilitate neuromuscular junction development

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Impaired excitation–contraction coupling in muscle fibres from the dynamin2^R465W mouse model of centronuclear myopathy

Impaired excitation–contraction coupling in muscle fibres from the dynamin2^R465W mouse model of centronuclear myopathy

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