Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle

Kerr, Jaclyn P.; Robison, Patrick; Shi, Guoli; Bogush, Alexey; Kempema, Aaron; Hexum, Joseph K.; Becerra, Natalia; Harki, Daniel A.; Martin, Stuart S.; Raiteri, Roberto; Prosser, Benjamin L.; Ward, Christopher W.

doi:10.1038/ncomms9526

Cited by 188 publications

(325 citation statements)

References 71 publications

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“…These could be induced by mechanical stress-dependent ROS formation. A number of factors favor this model: (i) We observed increased ROS/H 2 O 2 formation upon mechanically stressing paclitaxel-treated zebrafish larvae; (ii) mechanical stress triggers Nox-2-dependent "X-ROS" formation in cardiomyocytes and skeletal myofibers (48,49), and X-ROS formation is exacerbated in skeletal muscle of mice with Duchenne Muscular Dystrophy due to enhanced microtubule stiffness (49); and (iii) our RNAseq analysis shows that H 2 O 2 induces mmp13a expression in larval zebrafish (31). Δ373 mRNA into one-cell stage embryos and mechanical stress at 2 dpf (n = 3 biological replicates, 15 larvae per group).…”

Section: Discussionmentioning

confidence: 99%

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish

Lisse

Middleton

Pellegrini

et al. 2016

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

104

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Paclitaxel is a microtubule-stabilizing chemotherapeutic agent that is widely used in cancer treatment and in a number of curative and palliative regimens. Despite its beneficial effects on cancer, paclitaxel also damages healthy tissues, most prominently the peripheral sensory nervous system. The mechanisms leading to paclitaxelinduced peripheral neuropathy remain elusive, and therapies that prevent or alleviate this condition are not available. We established a zebrafish in vivo model to study the underlying mechanisms and to identify pharmacological agents that may be developed into therapeutics. Both adult and larval zebrafish displayed signs of paclitaxel neurotoxicity, including sensory axon degeneration and the loss of touch response in the distal caudal fin. Intriguingly, studies in zebrafish larvae showed that paclitaxel rapidly promotes epithelial damage and decreased mechanical stress resistance of the skin before induction of axon degeneration. Moreover, injured paclitaxel-treated zebrafish skin and scratch-wounded human keratinocytes (HEK001) display reduced healing capacity. Epithelial damage correlated with rapid accumulation of fluorescein-conjugated paclitaxel in epidermal basal keratinocytes, but not axons, and upregulation of matrix-metalloproteinase 13 (MMP-13, collagenase 3) in the skin. Pharmacological inhibition of MMP-13, in contrast, largely rescued paclitaxel-induced epithelial damage and neurotoxicity, whereas MMP-13 overexpression in zebrafish embryos rendered the skin vulnerable to injury under mechanical stress conditions. Thus, our studies provide evidence that the epidermis plays a critical role in this condition, and we provide a previously unidentified candidate for therapeutic interventions.aclitaxel is a microtubule-stabilizing chemotherapeutic agent that is widely used in the treatment of common cancers, including breast, ovarian, and lung cancer. Despite its promising anticancerous properties, paclitaxel also damages healthy tissues, most prominently peripheral axons of somatosensory neurons (reviewed in ref. 1). Paclitaxel-induced peripheral neuropathy initiates in the distal extremities and presents as neuropathic pain syndrome, temperature sensitivity, and paresthesia (tingling and numbness). Nerve biopsies from patients suggest that axon degeneration is the primary manifestation of this condition, followed by secondary demyelination and nerve fiber loss in severely affected patients (1, 2). Certain drugs have been shown in vitro and in vivo to protect against paclitaxel-induced nerve damage, including acetyl-L-carnitine, erythropoietin, alpha-lipoic acid, olesoxime, amifostine, nerve growth factor, and glutamate (reviewed in ref.3). However, so far, these agents have either not successfully passed clinical trials or merely alleviate symptoms such as pain without prevention (1). Thus, a better understanding of the underlying causes of paclitaxel-induced peripheral neuropathy is necessary and may help identify new candidate drugs with which to treat this condition.A widely...

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Section: Discussionmentioning

confidence: 99%

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish

Lisse

Middleton

Pellegrini

et al. 2016

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

104

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“…For example, Nox2 (gp91 phox ) and gp22 phox subunits are transmembrane proteins that occur as heterodimers and form part of a multi-subunit complex with other cytoplasmic components in the active form [65]. The active complex rapidly (<2 second resolution) responds to mechanical stress in both cardiac and skeletal muscles [13], and its activity is sensitive to sarcolemmal mechanical integrity and microtubule assembly [66]. GsMTx4-L inhibits the Ca 2+ influx triggered by ROS production [67].…”

Section: Discussionmentioning

confidence: 99%

GsMTx4-D is a cardioprotectant against myocardial infarction during ischemia and reperfusion

Wang

Sachs

et al. 2016

Journal of Molecular and Cellular Cardiology

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GsMTx4 is a selective inhibitor of cationic mechanosensitive ion channels (MSCs) and has helped establish the role of MSCs in cardiac physiology. Inhomogeneous local mechanical stresses due to hypercontracture and swelling during ischemic reperfusion injury (IRI) likely induce elevated MSC activity that can contribute to cation imbalance. The aim of this study was to determine if the D enantiomer of GsMTx4 can act as a cardioprotectant in a mouse IRI model. Ischemia and reperfusion involved ligating a coronary artery followed by release of the ligature. GsMTx4-D was tested by either acute intravenous injection during the ischemic event or by two day pretreatment by intraperitoneal injection, both methods achieving similar results. Based on pharmacokinetic studies, GsMTx4-D dosage was set to achieve expected plasma concentrations between 50 and 5000 nM and heart tissue concentrations between 1 and 200 nM by intravenous injection. Relative to vehicle injected animals, GsMTx4-D reduced infarct area by ~40% for acute and pretreated animals for both 20 and 45 min ischemic challenges. Many indicators of cardiac output were indistinguishable from sham-treated control hearts after GsMTx4-D treatment showing improvement at both 4 and 48 h post ischemia, and premature ventricular beats immediately following reperfusion were also significantly reduced. To determine if GsMTx4-D cardioprotection could act directly at the level of cardiomyocytes, we tested its effects in vitro on indicators of IRI damage like cation influx and activation of inflammatory kinases in isolated myocytes cultured under hypoxic conditions. Hypoxia challenged cardiomyocytes treated with 10 μM GsMTx4-D showed improved contractility and near normal contraction-related Ca2+ influx. GsMTx4-D inhibited indicators of ischemic damage such as the apoptotic signaling system JNK/c-Jun, but also inhibited the energy response signaling system Akt kinase. We conclude that GsMTx4-D is a potent cardioprotectant in vivo that may act directly on cardiomyocytes and potentially be useful in multidrug strategies to treat IRI.

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“…This network is dynamic, with microtubules polymerizing and depolymerizing continuously along a bundled framework (Oddoux et al, 2013). Microtubule bundles in muscles are involved in the stretch-activated production of reactive oxygen species (ROS), and alteration in this microtubule-dependent ROS production is a major defect in Duchenne muscular dystrophy (Kerr et al, 2015;Khairallah et al, 2012). Dynamic microtubule bundles might also be necessary for the morphogenesis of organelle subdomains such as the ER or SR subdomains (Cui-Wang et al, 2012;Vedrenne and Hauri, 2006).…”

Section: Discussionmentioning

confidence: 99%

Triadin and CLIMP-63 form a link between triads and microtubules in muscle cells

Osseni

Sébastien

Sarrault

et al. 2016

Journal of Cell Science

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In skeletal muscle, the triad is a structure comprising a transverse (T)-tubule and sarcoplasmic reticulum (SR) cisternae. Triads constitute the basis of excitation-contraction coupling as the cradle of the Ca 2+ release complex. We have shown previously that triadin, a member of this complex, has shaping properties on reticulum membrane and is indirectly involved in a link between triads and microtubules. We have identified here that CLIMP-63 (also known as CKAP4), as the partner of triadin, is responsible for this association of triads and microtubules. Triadin and CLIMP-63 interact through their respective luminal domains and the shaping properties of triadin depend on the capacity of CLIMP-63 to bind microtubules with its cytosolic portion. In skeletal muscle, CLIMP-63 is localized in the SR, including triads, and is associated with the Ca 2+ release complex through its interaction with triadin. Knockout of triadin in muscles results in the delocalization of CLIMP-63 from triads, its dissociation from the Ca 2+ release complex and a disorganization of the microtubule network. Our results suggest that the association of triadin and CLIMP-63 could be involved in the shaping of SR terminal cisternae and in the guidance of microtubules close to the triads.

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Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle

Cited by 188 publications

References 71 publications

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish

GsMTx4-D is a cardioprotectant against myocardial infarction during ischemia and reperfusion

Triadin and CLIMP-63 form a link between triads and microtubules in muscle cells

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