Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

Erik P Rader; Rolf Turk; Tobias Willer; Daniel Beltrán; Kei-Ichiro Inamori; Taylor A Peterson; Jeffrey Engle; Sally Prouty; Kiichiro Matsumura; Fumiaki Saito; Mary E Anderson; Kevin P Campbell

doi:10.1073/pnas.1605265113

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Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

Journal article

Open access

Peer reviewed

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

Erik P Rader, Rolf Turk, Tobias Willer, Daniel Beltrán, Kei-Ichiro Inamori, Taylor A Peterson, Jeffrey Engle, Sally Prouty, Kiichiro Matsumura, Fumiaki Saito, …

Proceedings of the National Academy of Sciences - PNAS, Vol.113(39), pp.10992-10997

09/27/2016

DOI: 10.1073/pnas.1605265113

PMCID: PMC5047148

PMID: 27625424

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Abstract

Dystroglycan (DG) is a highly expressed extracellular matrix receptor that is linked to the cytoskeleton in skeletal muscle. DG is critical for the function of skeletal muscle, and muscle with primary defects in the expression and/or function of DG throughout development has many pathological features and a severe muscular dystrophy phenotype. In addition, reduction in DG at the sarcolemma is a common feature in muscle biopsies from patients with various types of muscular dystrophy. However, the consequence of disrupting DG in mature muscle is not known. Here, we investigated muscles of transgenic mice several months after genetic knockdown of DG at maturity. In our study, an increase in susceptibility to contraction-induced injury was the first pathological feature observed after the levels of DG at the sarcolemma were reduced. The contraction-induced injury was not accompanied by increased necrosis, excitation-contraction uncoupling, or fragility of the sarcolemma. Rather, disruption of the sarcomeric cytoskeleton was evident as reduced passive tension and decreased titin immunostaining. These results reveal a role for DG in maintaining the stability of the sarcomeric cytoskeleton during contraction and provide mechanistic insight into the cause of the reduction in strength that occurs in muscular dystrophy after lengthening contractions.

Excitation Contraction Coupling - drug effects

Isometric Contraction - drug effects

Sarcomeres - drug effects

Sarcomeres - metabolism

RNA, Messenger - genetics

Dystroglycans - metabolism

Organ Size

Male

RNA, Messenger - metabolism

Mice, Knockout

Necrosis

Animals

Connectin - metabolism

Muscle Contraction - drug effects

Muscle, Skeletal - drug effects

Muscle, Skeletal - physiopathology

Tamoxifen - pharmacology

Cytoskeleton - metabolism

Female

Muscle, Skeletal - pathology

Sarcolemma - metabolism

Cytoskeleton - drug effects

Details

Title: Subtitle: Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle
Creators: Erik P Rader - Howard Hughes Medical Institute, The University of Iowa, Iowa City, IA 52242; Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA 52242; Department of Neurology, The University of Iowa, Iowa City, IA 52242; Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242
Rolf Turk - Howard Hughes Medical Institute, The University of Iowa, Iowa City, IA 52242; Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA 52242; Department of Neurology, The University of Iowa, Iowa City, IA 52242; Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242
Tobias Willer - Howard Hughes Medical Institute, The University of Iowa, Iowa City, IA 52242; Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA 52242; Department of Neurology, The University of Iowa, Iowa City, IA 52242; Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242
Daniel Beltrán - Howard Hughes Medical Institute, The University of Iowa, Iowa City, IA 52242; Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA 52242; Department of Neurology, The University of Iowa, Iowa City, IA 52242; Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242
Kei-Ichiro Inamori - Howard Hughes Medical Institute, The University of Iowa, Iowa City, IA 52242; Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA 52242; Department of Neurology, The University of Iowa, Iowa City, IA 52242; Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242; Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi 981-8558, Japan
Taylor A Peterson - Howard Hughes Medical Institute, The University of Iowa, Iowa City, IA 52242; Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA 52242; Department of Neurology, The University of Iowa, Iowa City, IA 52242; Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242
Jeffrey Engle - Howard Hughes Medical Institute, The University of Iowa, Iowa City, IA 52242; Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA 52242; Department of Neurology, The University of Iowa, Iowa City, IA 52242; Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242
Sally Prouty - Howard Hughes Medical Institute, The University of Iowa, Iowa City, IA 52242; Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA 52242; Department of Neurology, The University of Iowa, Iowa City, IA 52242; Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242
Kiichiro Matsumura - Department of Neurology, Teikyo University School of Medicine, Itabashi-ku, Tokoyo 173-8605, Japan
Fumiaki Saito - Department of Neurology, Teikyo University School of Medicine, Itabashi-ku, Tokoyo 173-8605, Japan
Mary E Anderson - Howard Hughes Medical Institute, The University of Iowa, Iowa City, IA 52242; Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA 52242; Department of Neurology, The University of Iowa, Iowa City, IA 52242; Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242
Kevin P Campbell - Howard Hughes Medical Institute, The University of Iowa, Iowa City, IA 52242; Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA 52242; Department of Neurology, The University of Iowa, Iowa City, IA 52242; Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242; kevin-campbell@uiowa.edu
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.113(39), pp.10992-10997
DOI: 10.1073/pnas.1605265113
PMID: 27625424
PMCID: PMC5047148
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences; United States
Grant note: T32 HL007121 / NHLBI NIH HHS U54 NS053672 / NINDS NIH HHS
Language: English
Date published: 09/27/2016
Academic Unit: Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984020645502771

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