Evidence map›Paper›PMID 26605308›Full record

ArticleAnnals of translational medicine2015

Muscle pathology, limb strength, walking gait, respiratory function and neurological impairment establish disease progression in the p.N155K canine model of X-linked myotubular myopathy.

Melissa A Goddard, David L Mack, Stefan M Czerniecki, Valerie E Kelly, Jessica M Snyder, Robert W Grange, Michael W Lawlor, Barbara K Smith, Alan H Beggs, Martin K Childers

Erratum issuedAbstract read
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Article in Annals of translational medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
1.2field-weighted citation impact, top 22% 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

8 citing papers in PubMed, 12 citations in OpenAlex.

  1. Article
  2. Article
  3. AAV-Mediated Gene Transfer Restores a Normal Muscle Transcriptome in a Canine Model of X-Linked Myotubular Myopathy.Molecular therapy : the journal of the American Society of Gene Therapy · 2020
    Article
  4. Article
  5. Article
  6. Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs.Molecular therapy : the journal of the American Society of Gene Therapy · 2017
    Article
  7. Article
  8. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

10 authors at 1 institution in 1 country.

Melissa A Goddard1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
David L Mack1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Stefan M Czerniecki1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Valerie E Kelly1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Jessica M Snyder1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Robert W Grange1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Michael W Lawlor1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Barbara K Smith1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Alan H Beggs1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Martin K Childers1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
University of Washington · US

Funding

Vector Research Resource CoreU54AR065139 · NIAMS · UNIVERSITY OF WASHINGTON · PI CHAMBERLAIN, JEFFREY S · 2014 to 2017
$6.3M
SARCOMERIC PROTEINS IN NORMAL AND DISEASED MUSCLER01AR044345 · NIAMS · CHILDREN'S HOSPITAL BOSTON · PI BEGGS, ALAN H. · 1997 to 2017
$5.3M
Gene therapy in canine myotubular myopathy for clinical translationR01HL115001 · NHLBI · UNIVERSITY OF WASHINGTON · PI CHILDERS, MARTIN K · 2013 to 2017
$3.9M
Mechanisms and efficacy of myostatin inhibition in myotubular myopathyK08AR059750 · NIAMS · MEDICAL COLLEGE OF WISCONSIN · PI LAWLOR, MICHAEL WILLIAM · 2010 to 2014
$641k
Establishing endpoints in canine myotubular myopathy for clinical translationR21AR064503 · NIAMS · UNIVERSITY OF WASHINGTON · PI CHILDERS, MARTIN K · 2012 to 2013
$389k
NHLBI NIH HHS R01 HL115001NIAMS NIH HHS K08 AR059750NIAMS NIH HHS L40 AR057721NIAMS NIH HHS R01 AR044345NIAMS NIH HHS R21 AR064503NIAMS NIH HHS U54 AR065139
6 · The paper itself

Abstract

backgroundLoss-of-function mutations in the myotubularin (MTM1) gene cause X-linked myotubular myopathy (XLMTM), a fatal, inherited pediatric disease that affects the entire skeletal musculature. Labrador retriever dogs carrying an MTM1 missense mutation exhibit strongly reduced synthesis of myotubularin, the founder member of a lipid phosphatase required for normal skeletal muscle function. The resulting canine phenotype resembles that of human patients with comparably severe mutations, and survival does not normally exceed 4 months.

methodsWe studied MTM1 mutant dogs (n=7) and their age-matched control littermates (n=6) between the ages of 10 and 25 weeks. Investigators blinded to the animal identities sequentially measured limb muscle pathology, fore- and hind limb strength, walking gait, respiratory function and neurological impairment.

resultsMTM1-mutant puppies display centrally-nucleated myofibers of reduced size and disrupted sarcotubular architecture progressing until the end of life, an average of 17 weeks. In-life measures of fore- and hind limb strength establish the rate at which XLMTM muscles weaken, and their corresponding decrease in gait velocity and stride length. Pulmonary function tests in affected dogs reveal a right-shifted relationship between peak inspiratory flow (PIF) and inspiratory time (TI); neurological assessments indicate that affected puppies as young as 10 weeks show early signs of neurological impairment (neurological severity score, NSS =8.6±0.9) with progressive decline (NSS =5.6±1.7 at 17 weeks-of-age).

conclusionsOur findings document the rate of disease progression in a large animal model of XLMTM and lay a foundation for preclinical studies.

Indexed as

Animal modelsdogmuscle diseasemuscular dystrophymyopathymyotubular myopathy

Identifiers

PMID26605308
PMCPMC4630545
OpenAlexW1857640949

What OpenQuestion holds

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Registered trials

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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.