High-throughput screening identifies modulators of sarcospan that stabilize muscle cells and exhibit activity in the mouse model of Duchenne muscular dystrophy.

Abstract:

BACKGROUND:Duchenne muscular dystrophy (DMD) is a degenerative muscle disease caused by mutations in the dystrophin gene. Loss of dystrophin prevents the formation of a critical connection between the muscle cell membrane and the extracellular matrix. Overexpression of sarcospan (SSPN) in the mouse model of DMD restores the membrane connection and reduces disease severity, making SSPN a promising therapeutic target for pharmacological upregulation. METHODS:Using a previously described cell-based promoter reporter assay of SSPN gene expression (hSSPN-EGFP), we conducted high-throughput screening on libraries of over 200,000 curated small molecules to identify SSPN modulators. The hits were validated in both hSSPN-EGFP and hSSPN-luciferase reporter cells. Hit selection was conducted on dystrophin-deficient mouse and human myotubes with assessments of (1) SSPN gene expression using quantitative PCR and (2) SSPN protein expression using immunoblotting and an ELISA. A membrane stability assay using osmotic shock was used to validate the functional effects of treatment followed by cell surface biotinylation to label cell surface proteins. Dystrophin-deficient mdx mice were treated with compound, and muscle was subjected to quantitative PCR to assess SSPN gene expression. RESULTS:We identified and validated lead compounds that increased SSPN gene and protein expression in dystrophin-deficient mouse and human muscle cells. The lead compound OT-9 increased cell membrane localization of compensatory laminin-binding adhesion complexes and improved membrane stability in DMD myotubes. We demonstrated that the membrane stabilizing benefit is dependent on SSPN. Intramuscular injection of OT-9 in the mouse model of DMD increased SSPN gene expression. CONCLUSIONS:This study identifies a pharmacological approach to treat DMD and sets the path for the development of SSPN-based therapies.

journal_name

Skelet Muscle

journal_title

Skeletal muscle

authors

Shu C,Parfenova L,Mokhonova E,Collado JR,Damoiseaux R,Campagna J,John V,Crosbie RH

doi

10.1186/s13395-020-00244-3

subject

Has Abstract

pub_date

2020-09-18 00:00:00

pages

26

issue

1

issn

2044-5040

pii

10.1186/s13395-020-00244-3

journal_volume

10

pub_type

杂志文章
  • Complementary NAD+ replacement strategies fail to functionally protect dystrophin-deficient muscle.

    abstract:BACKGROUND:Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder stemming from a loss of functional dystrophin. Current therapeutic options for DMD are limited, as small molecule modalities remain largely unable to decrease the incidence or mitigate the consequences of repetitive mechanical insults...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-020-00249-y

    authors: Frederick DW,McDougal AV,Semenas M,Vappiani J,Nuzzo A,Ulrich JC,Becherer JD,Preugschat F,Stewart EL,Sévin DC,Kramer HF

    更新日期:2020-10-22 00:00:00

  • T-tubule biogenesis and triad formation in skeletal muscle and implication in human diseases.

    abstract:: In skeletal muscle, the excitation-contraction (EC) coupling machinery mediates the translation of the action potential transmitted by the nerve into intracellular calcium release and muscle contraction. EC coupling requires a highly specialized membranous structure, the triad, composed of a central T-tubule surround...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/2044-5040-1-26

    authors: Al-Qusairi L,Laporte J

    更新日期:2011-07-13 00:00:00

  • Unexpected evolutionarily conserved rapid effects of viral infection on oxytocin receptor and TGF-β/pSmad3.

    abstract:BACKGROUND:shRNA lentiviral vectors are extensively used for gene knockdowns in mammalian cells, and non-target shRNAs typically are considered the proper experimental control for general changes caused by RNAi. However, the effects of non-target lentivirus controls on the modulation of cell signaling pathways remain l...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-017-0125-y

    authors: Liu Y,Conboy I

    更新日期:2017-05-15 00:00:00

  • The golden retriever model of Duchenne muscular dystrophy.

    abstract::Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the DMD gene and loss of the protein dystrophin. The absence of dystrophin leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to...

    journal_title:Skeletal muscle

    pub_type: 杂志文章,评审

    doi:10.1186/s13395-017-0124-z

    authors: Kornegay JN

    更新日期:2017-05-19 00:00:00

  • Induction of the nicotinamide riboside kinase NAD+ salvage pathway in a model of sarcoplasmic reticulum dysfunction.

    abstract:BACKGROUND:Hexose-6-Phosphate Dehydrogenase (H6PD) is a generator of NADPH in the Endoplasmic/Sarcoplasmic Reticulum (ER/SR). Interaction of H6PD with 11β-hydroxysteroid dehydrogenase type 1 provides NADPH to support oxo-reduction of inactive to active glucocorticoids, but the wider understanding of H6PD in ER/SR NAD(P...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-019-0216-z

    authors: Doig CL,Zielinska AE,Fletcher RS,Oakey LA,Elhassan YS,Garten A,Cartwright D,Heising S,Alsheri A,Watson DG,Prehn C,Adamski J,Tennant DA,Lavery GG

    更新日期:2020-02-19 00:00:00

  • Ca(2+) permeation and/or binding to CaV1.1 fine-tunes skeletal muscle Ca(2+) signaling to sustain muscle function.

    abstract:BACKGROUND:Ca(2+) influx through CaV1.1 is not required for skeletal muscle excitation-contraction coupling, but whether Ca(2+) permeation through CaV1.1 during sustained muscle activity plays a functional role in mammalian skeletal muscle has not been assessed. METHODS:We generated a mouse with a Ca(2+) binding and/o...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-014-0027-1

    authors: Lee CS,Dagnino-Acosta A,Yarotskyy V,Hanna A,Lyfenko A,Knoblauch M,Georgiou DK,Poché RA,Swank MW,Long C,Ismailov II,Lanner J,Tran T,Dong K,Rodney GG,Dickinson ME,Beeton C,Zhang P,Dirksen RT,Hamilton SL

    更新日期:2015-01-29 00:00:00

  • Regions of ryanodine receptors that influence activation by the dihydropyridine receptor β1a subunit.

    abstract:BACKGROUND:Although excitation-contraction (EC) coupling in skeletal muscle relies on physical activation of the skeletal ryanodine receptor (RyR1) Ca(2+) release channel by dihydropyridine receptors (DHPRs), the activation pathway between the DHPR and RyR1 remains unknown. However, the pathway includes the DHPR β1a su...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-015-0049-3

    authors: Rebbeck RT,Willemse H,Groom L,Casarotto MG,Board PG,Beard NA,Dirksen RT,Dulhunty AF

    更新日期:2015-07-22 00:00:00

  • TRAPPC11 and GOSR2 mutations associate with hypoglycosylation of α-dystroglycan and muscular dystrophy.

    abstract:BACKGROUND:Transport protein particle (TRAPP) is a supramolecular protein complex that functions in localizing proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in muscle disease by virtue of homozygous and compound heterozygous deleterious mutations being identified in individuals with limb g...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-018-0163-0

    authors: Larson AA,Baker PR 2nd,Milev MP,Press CA,Sokol RJ,Cox MO,Lekostaj JK,Stence AA,Bossler AD,Mueller JM,Prematilake K,Tadjo TF,Williams CA,Sacher M,Moore SA

    更新日期:2018-05-31 00:00:00

  • Visualization of PAX7 protein dynamics in muscle satellite cells in a YFP knock-in-mouse line.

    abstract:BACKGROUND:Satellite cells are residential muscle stem cells that express a paired box protein, PAX7. RESULTS:Here, we report a knock-in mouse line expressing a PAX7-enhanced yellow fluorescent protein (YFP) fusion protein that enables visualization of PAX7 protein dynamics in living satellite cells through YFP fluore...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-018-0174-x

    authors: Kitajima Y,Ono Y

    更新日期:2018-08-24 00:00:00

  • Skeletal muscle characteristics are preserved in hTERT/cdk4 human myogenic cell lines.

    abstract:BACKGROUND:hTERT/cdk4 immortalized myogenic human cell lines represent an important tool for skeletal muscle research, being used as therapeutically pertinent models of various neuromuscular disorders and in numerous fundamental studies of muscle cell function. However, the cell cycle is linked to other cellular proces...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-016-0115-5

    authors: Thorley M,Duguez S,Mazza EMC,Valsoni S,Bigot A,Mamchaoui K,Harmon B,Voit T,Mouly V,Duddy W

    更新日期:2016-12-08 00:00:00

  • Linkages between changes in the 3D organization of the genome and transcription during myotube differentiation in vitro.

    abstract:BACKGROUND:The spatial organization of eukaryotic genomes facilitates and reflects the underlying nuclear processes that are occurring in the cell. As such, the spatial organization of a genome represents a window on the genome biology that enables analysis of the nuclear regulatory processes that contribute to mammali...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-017-0122-1

    authors: Doynova MD,Markworth JF,Cameron-Smith D,Vickers MH,O'Sullivan JM

    更新日期:2017-04-05 00:00:00

  • RNA-sequencing reveals altered skeletal muscle contraction, E3 ligases, autophagy, apoptosis, and chaperone expression in patients with critical illness myopathy.

    abstract:BACKGROUND:Critical illness myopathy (CIM) is associated with severe skeletal muscle wasting and impaired function in intensive care unit (ICU) patients. The mechanisms underlying CIM remain incompletely understood. To elucidate the biological activities occurring at the transcriptional level in the skeletal muscle of ...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-019-0194-1

    authors: Llano-Diez M,Fury W,Okamoto H,Bai Y,Gromada J,Larsson L

    更新日期:2019-04-16 00:00:00

  • Dietary supplementation with ketoacids protects against CKD-induced oxidative damage and mitochondrial dysfunction in skeletal muscle of 5/6 nephrectomised rats.

    abstract:BACKGROUND:A low-protein diet supplemented with ketoacids (LPD + KA) maintains the nutritional status of patients with chronic kidney disease (CKD). Oxidative damage and mitochondrial dysfunction associated with the upregulation of p66SHC and FoxO3a have been shown to contribute to muscle atrophy. This study aimed to d...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-018-0164-z

    authors: Wang D,Wei L,Yang Y,Liu H

    更新日期:2018-05-31 00:00:00

  • Decrease of myofiber branching via muscle-specific expression of the olfactory receptor mOR23 in dystrophic muscle leads to protection against mechanical stress.

    abstract:BACKGROUND:Abnormal branched myofibers within skeletal muscles are commonly found in diverse animal models of muscular dystrophy as well as in patients. Branched myofibers from dystrophic mice are more susceptible to break than unbranched myofibers suggesting that muscles containing a high percentage of these myofibers...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-016-0077-7

    authors: Pichavant C,Burkholder TJ,Pavlath GK

    更新日期:2016-01-21 00:00:00

  • Differential myofiber-type transduction preference of adeno-associated virus serotypes 6 and 9.

    abstract:BACKGROUND:Gene therapy strategies are promising therapeutic options for monogenic muscular dystrophies, with several currently underways. The adeno-associated viral (AAV) vector is among the most effective gene delivery systems. However, transduction efficiency in skeletal muscles varies between AAV serotypes, with th...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-015-0064-4

    authors: Riaz M,Raz Y,Moloney EB,van Putten M,Krom YD,van der Maarel SM,Verhaagen J,Raz V

    更新日期:2015-11-10 00:00:00

  • Overexpression of the double homeodomain protein DUX4c interferes with myofibrillogenesis and induces clustering of myonuclei.

    abstract:BACKGROUND:Facioscapulohumeral muscular dystrophy (FSHD) is associated with DNA hypomethylation at the 4q35 D4Z4 repeat array. Both the causal gene DUX4 and its homolog DUX4c are induced. DUX4c is immunodetected in every myonucleus of proliferative cells, while DUX4 is present in only 1/1000 of myonuclei where it initi...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-017-0148-4

    authors: Vanderplanck C,Tassin A,Ansseau E,Charron S,Wauters A,Lancelot C,Vancutsem K,Laoudj-Chenivesse D,Belayew A,Coppée F

    更新日期:2018-01-12 00:00:00

  • Correction to: Expressing a Z-disk nebulin fragment innebulin-deficient mouse muscle: effects on muscle structure and function.

    abstract::Following the publication of this paper [1], it was brought to the authors' attention that one of the contributing authors was left off of the paper. The authors apologize for the unfortunate oversight. In this correction paper, they have included Dr. Paola Tonino in the author list section. ...

    journal_title:Skeletal muscle

    pub_type: 已发布勘误

    doi:10.1186/s13395-020-00223-8

    authors: Li F,Kolb J,Crudele J,Tonino P,Hourani Z,Smith JE 3rd,Chamberlain JS,Granzier H

    更新日期:2020-04-20 00:00:00

  • MuscleJ: a high-content analysis method to study skeletal muscle with a new Fiji tool.

    abstract:BACKGROUND:Skeletal muscle has the capacity to adapt to environmental changes and regenerate upon injury. To study these processes, most experimental methods use quantification of parameters obtained from images of immunostained skeletal muscle. Muscle cross-sectional area, fiber typing, localization of nuclei within t...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-018-0171-0

    authors: Mayeuf-Louchart A,Hardy D,Thorel Q,Roux P,Gueniot L,Briand D,Mazeraud A,Bouglé A,Shorte SL,Staels B,Chrétien F,Duez H,Danckaert A

    更新日期:2018-08-06 00:00:00

  • Myofiber branching rather than myofiber hyperplasia contributes to muscle hypertrophy in mdx mice.

    abstract:BACKGROUND:Muscle hypertrophy in the mdx mouse model of Duchenne muscular dystrophy (DMD) can partially compensate for the loss of dystrophin by maintaining peak force production. Histopathology examination of the hypertrophic muscles suggests the hypertrophy primarily results from the addition of myofibers, and is acc...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/2044-5040-4-10

    authors: Faber RM,Hall JK,Chamberlain JS,Banks GB

    更新日期:2014-05-23 00:00:00

  • Exogenous expression of the glycosyltransferase LARGE1 restores α-dystroglycan matriglycan and laminin binding in rhabdomyosarcoma.

    abstract:BACKGROUND:α-Dystroglycan is the highly glycosylated component of the dystrophin-glycoprotein complex (DGC) that binds with high-affinity to extracellular matrix (ECM) proteins containing laminin-G-like (LG) domains via a unique heteropolysaccharide [-GlcA-beta1,3-Xyl-alpha1,3-]n called matriglycan. Changes in expressi...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-019-0195-0

    authors: Beltrán D,Anderson ME,Bharathy N,Settelmeyer TP,Svalina MN,Bajwa Z,Shern JF,Gultekin SH,Cuellar MA,Yonekawa T,Keller C,Campbell KP

    更新日期:2019-05-04 00:00:00

  • Skeletal muscle interleukin 15 promotes CD8(+) T-cell function and autoimmune myositis.

    abstract:BACKGROUND:Interleukin 15 (IL-15) is thought to be abundant in the skeletal muscle under steady state conditions based on RNA expression; however, the IL-15 RNA level may not reflect the protein level due to post-transcriptional regulation. Although exogenous protein treatment and overexpression studies indicated IL-15...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-015-0058-2

    authors: Huang PL,Hou MS,Wang SW,Chang CL,Liou YH,Liao NS

    更新日期:2015-09-28 00:00:00

  • Laminin 521 maintains differentiation potential of mouse and human satellite cell-derived myoblasts during long-term culture expansion.

    abstract:BACKGROUND:Large-scale expansion of myogenic progenitors is necessary to support the development of high-throughput cellular assays in vitro and to advance genetic engineering approaches necessary to develop cellular therapies for rare muscle diseases. However, optimization has not been performed in order to maintain t...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-016-0116-4

    authors: Penton CM,Badarinarayana V,Prisco J,Powers E,Pincus M,Allen RE,August PR

    更新日期:2016-12-13 00:00:00

  • Establishment of clonal myogenic cell lines from severely affected dystrophic muscles - CDK4 maintains the myogenic population.

    abstract:BACKGROUND:A hallmark of muscular dystrophies is the replacement of muscle by connective tissue. Muscle biopsies from patients severely affected with facioscapulohumeral muscular dystrophy (FSHD) may contain few myogenic cells. Because the chromosomal contraction at 4q35 linked to FSHD is thought to cause a defect with...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/2044-5040-1-12

    authors: Stadler G,Chen JC,Wagner K,Robin JD,Shay JW,Emerson CP Jr,Wright WE

    更新日期:2011-03-08 00:00:00

  • Treating cancer cachexia to treat cancer.

    abstract::Skeletal muscle wasting is a major component of cachectic states found in a variety of disease settings, including cancer. As increasing caloric intake often provides little benefit in combating muscle loss in cachectic patients, a major research focus has been to develop strategies stimulating muscle anabolic pathway...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/2044-5040-1-2

    authors: Lee SJ,Glass DJ

    更新日期:2011-01-24 00:00:00

  • Defective angiogenesis in CXCL12 mutant mice impairs skeletal muscle regeneration.

    abstract:BACKGROUND:During muscle regeneration, the chemokine CXCL12 (SDF-1) and the synthesis of some specific heparan sulfates (HS) have been shown to be critical. CXCL12 activity has been shown to be heavily influenced by its binding to extracellular glycosaminoglycans (GAG) by modulating its presentation to its receptors an...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-019-0210-5

    authors: Hardy D,Fefeu M,Besnard A,Briand D,Gasse P,Arenzana-Seisdedos F,Rocheteau P,Chrétien F

    更新日期:2019-09-18 00:00:00

  • The role of Nrf2 in acute and chronic muscle injury.

    abstract::The nuclear factor erythroid 2-related factor 2 (Nrf2) is considered as a master cytoprotective factor regulating the expression of genes encoding anti-oxidant, anti-inflammatory, and detoxifying proteins. The role of Nrf2 in the pathophysiology of skeletal muscles has been evaluated in different experimental models, ...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-020-00255-0

    authors: Bronisz-Budzyńska I,Kozakowska M,Podkalicka P,Kachamakova-Trojanowska N,Łoboda A,Dulak J

    更新日期:2020-12-08 00:00:00

  • Absence of physiological Ca2+ transients is an initial trigger for mitochondrial dysfunction in skeletal muscle following denervation.

    abstract:BACKGROUND:Motor neurons control muscle contraction by initiating action potentials in muscle. Denervation of muscle from motor neurons leads to muscle atrophy, which is linked to mitochondrial dysfunction. It is known that denervation promotes mitochondrial reactive oxygen species (ROS) production in muscle, whereas t...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-017-0123-0

    authors: Karam C,Yi J,Xiao Y,Dhakal K,Zhang L,Li X,Manno C,Xu J,Li K,Cheng H,Ma J,Zhou J

    更新日期:2017-04-10 00:00:00

  • Late-onset megaconial myopathy in mice lacking group I Paks.

    abstract:BACKGROUND:Group I Paks are serine/threonine kinases that function as major effectors of the small GTPases Rac1 and Cdc42, and they regulate cytoskeletal dynamics, cell polarity, and transcription. We previously demonstrated that Pak1 and Pak2 function redundantly to promote skeletal myoblast differentiation during pos...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-019-0191-4

    authors: Joseph GA,Hung M,Goel AJ,Hong M,Rieder MK,Beckmann ND,Serasinghe MN,Chipuk JE,Devarakonda PM,Goldhamer DJ,Aldana-Hernandez P,Curtis J,Jacobs RL,Krauss RS

    更新日期:2019-02-21 00:00:00

  • Mitochondrial dysfunction and consequences in calpain-3-deficient muscle.

    abstract:BACKGROUND:Nonsense or loss-of-function mutations in the non-lysosomal cysteine protease calpain-3 result in limb-girdle muscular dystrophy type 2A (LGMD2A). While calpain-3 is implicated in muscle cell differentiation, sarcomere formation, and muscle cytoskeletal remodeling, the physiological basis for LGMD2A has rema...

    journal_title:Skeletal muscle

    pub_type: 杂志文章

    doi:10.1186/s13395-020-00254-1

    authors: Jahnke VE,Peterson JM,Van Der Meulen JH,Boehler J,Uaesoontrachoon K,Johnston HK,Defour A,Phadke A,Yu Q,Jaiswal JK,Nagaraju K

    更新日期:2020-12-11 00:00:00

  • Muscle spindle function in healthy and diseased muscle.

    abstract::Almost every muscle contains muscle spindles. These delicate sensory receptors inform the central nervous system (CNS) about changes in the length of individual muscles and the speed of stretching. With this information, the CNS computes the position and movement of our extremities in space, which is a requirement for...

    journal_title:Skeletal muscle

    pub_type: 杂志文章,评审

    doi:10.1186/s13395-020-00258-x

    authors: Kröger S,Watkins B

    更新日期:2021-01-07 00:00:00