Evidence map›Paper›PMID 32948250›Full record

ArticleSkeletal muscle2020

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

Cynthia Shu, Liubov Parfenova, Ekaterina Mokhonova, Judd R Collado, Robert Damoiseaux, Jesus Campagna, Varghese John, Rachelle H Crosbie

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Skeletal muscle, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
0.3field-weighted citation impact, top 46% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed, 5 citations in OpenAlex.

  1. Review
  2. Article
  3. High-Throughput Screening to Identify Modulators of Sarcospan.Methods in molecular biology (Clifton, N.J.) · 2023
    Article
  4. Review
  5. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 2 institutions in 1 country.

Cynthia ShuMolecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA.
Liubov ParfenovaDepartment of Integrative Biology and Physiology, University of California Los Angeles, 610 Charles E. Young Drive East, Terasaki Life Sciences Building, Los Angeles, CA, 90095, USA.
Ekaterina MokhonovaDepartment of Integrative Biology and Physiology, University of California Los Angeles, 610 Charles E. Young Drive East, Terasaki Life Sciences Building, Los Angeles, CA, 90095, USA.
Judd R ColladoDepartment of Integrative Biology and Physiology, University of California Los Angeles, 610 Charles E. Young Drive East, Terasaki Life Sciences Building, Los Angeles, CA, 90095, USA.
Robert DamoiseauxDepartment of Molecular and Medicinal Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.
Jesus CampagnaDepartment of Neurology, David Geffen School of Medicine, University of California Los Angeles, 610 Charles E. Young Drive East, Terasaki Life Sciences Building, Los Angeles, CA, 90095, USA.
Varghese JohnDepartment of Neurology, David Geffen School of Medicine, University of California Los Angeles, 610 Charles E. Young Drive East, Terasaki Life Sciences Building, Los Angeles, CA, 90095, USA.
Rachelle H CrosbieMolecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. rcrosbie@physci.ucla.edu.ORCID 0000-0001-6630-6713
University of California, Los Angeles · USCalifornia NanoSystems Institute · US

Funding

Women's CancersP30CA016042 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Samuel Wheeler French · 1985 to 2026
$134.5M
Structure-Function Analysis of SarcospanR01AR048179 · NIAMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CROSBIE, RACHELLE HOPE · 2001 to 2023
$6.9M
UCLA Muscular Dystrophy Core CenterP30AR057230 · NIAMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI SPENCER, MELISSA JAN · 2009 to 2018
$6.2M
Muscle Cell Biology, Pathophysiology, and TherapeuticsT32AR065972 · NIAMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Rachelle Hope Crosbie, THOMAS A. RANDO · 2016 to 2026
$3.9M
Restoration of muscle cell adhesion to treat cardiomyopathy in muscular dystrophyR01HL126204 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CROSBIE, RACHELLE HOPE · 2016 to 2019
$1.5M
NCI NIH HHS P30 CA016042NHLBI NIH HHS R01 HL126204NIAMS NIH HHS P30 AR057230NIAMS NIH HHS R01 AR048179NIAMS NIH HHS T32 AR065972
6 · The paper itself

Abstract

backgroundDuchenne 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.

methodsUsing 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.

resultsWe 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.

conclusionsThis study identifies a pharmacological approach to treat DMD and sets the path for the development of SSPN-based therapies.

Indexed as

AnimalsCell LineDrug DiscoveryHigh-Throughput Screening AssaysHumansMaleMembrane ProteinsMiceMice, Inbred C57BLMice, Inbred mdxMuscle Fibers, SkeletalMuscular Dystrophy, DuchenneNeoplasm ProteinsSmall Molecule LibrariesMembrane ProteinsNeoplasm ProteinsSmall Molecule LibrariesSspn protein, mouseDrug discoveryDuchenne muscular dystrophyDystrophinHigh-throughput screenSarcolemmaSarcospanSmall molecules

Identifiers

PMID32948250
PMCPMC7499884
OpenAlexW3087758157

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.