Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the γ-sarcoglycan-null mouse

Jessica C de Greef; Rebecca Hamlyn; Braden S Jensen; Raul O'Campo Landa; Jennifer R Levy; Kazuhiro Kobuke; Kevin P Campbell

doi:10.1093/hmg/ddw018

Back

Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the γ-sarcoglycan-null mouse

Journal article

Open access

Peer reviewed

Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the γ-sarcoglycan-null mouse

Jessica C de Greef, Rebecca Hamlyn, Braden S Jensen, Raul O'Campo Landa, Jennifer R Levy, Kazuhiro Kobuke and Kevin P Campbell

Human molecular genetics, Vol.25(7), pp.1357-1369

04/01/2016

DOI: 10.1093/hmg/ddw018

PMCID: PMC4787905

PMID: 26908621

Files and links (1)

url

https://doi.org/10.1093/hmg/ddw018View

Published (Version of record) Open Access

Abstract

Muscular dystrophy is characterized by progressive skeletal muscle weakness and dystrophic muscle exhibits degeneration and regeneration of muscle cells, inflammation and fibrosis. Skeletal muscle fibrosis is an excessive deposition of components of the extracellular matrix including an accumulation of Collagen VI. We hypothesized that a reduction of Collagen VI in a muscular dystrophy model that presents with fibrosis would result in reduced muscle pathology and improved muscle function. To test this hypothesis, we crossed γ-sarcoglycan-null mice, a model of limb-girdle muscular dystrophy type 2C, with a Col6a2-deficient mouse model. We found that the resulting γ-sarcoglycan-null/Col6a2Δex5 mice indeed exhibit reduced muscle pathology compared with γ-sarcoglycan-null mice. Specifically, fewer muscle fibers are degenerating, fiber size varies less, Evans blue dye uptake is reduced and serum creatine kinase levels are lower. Surprisingly, in spite of this reduction in muscle pathology, muscle function is not significantly improved. In fact, grip strength and maximum isometric tetanic force are even lower in γ-sarcoglycan-null/Col6a2Δex5 mice than in γ-sarcoglycan-null mice. In conclusion, our results reveal that Collagen VI-mediated fibrosis contributes to skeletal muscle pathology in γ-sarcoglycan-null mice. Importantly, however, our data also demonstrate that a reduction in skeletal muscle pathology does not necessarily lead to an improvement of skeletal muscle function, and this should be considered in future translational studies.

Animals

Muscular Dystrophy, Animal - physiopathology

Sarcoglycanopathies - metabolism

Down-Regulation

Collagen Type VI - metabolism

Muscular Dystrophy, Animal - metabolism

Sarcoglycanopathies - pathology

Sarcoglycanopathies - physiopathology

Muscle, Skeletal - metabolism

Mice

Muscular Dystrophy, Animal - pathology

Mice, Knockout

Details

Title: Subtitle: Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the γ-sarcoglycan-null mouse
Creators: Jessica C de Greef - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology and Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Rebecca Hamlyn - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology and Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Braden S Jensen - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology and Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Raul O'Campo Landa - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology and Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Jennifer R Levy - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology and Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Kazuhiro Kobuke - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology and Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Kevin P Campbell - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology and Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA kevin-campbell@uiowa.edu
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.25(7), pp.1357-1369
DOI: 10.1093/hmg/ddw018
PMID: 26908621
PMCID: PMC4787905
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: England
Grant note: T32HL007121 / NHLBI NIH HHS U54 NS053672 / NINDS NIH HHS 1U54NS053672 / NINDS NIH HHS Howard Hughes Medical Institute
Language: English
Date published: 04/01/2016
Academic Unit: Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984020609102771

Metrics

18 Record Views

16 Times Cited - Web of Science