Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle.
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.
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;
Erik P
EP
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
R
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
T
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
D
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; Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi 981-8558, Japan;
Kei-Ichiro
K
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;
Taylor A
TA
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
J
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
S
Prouty
Department of Neurology, Teikyo University School of Medicine, Itabashi-ku, Tokoyo 173-8605, Japan.
Kiichiro
K
Matsumura
Department of Neurology, Teikyo University School of Medicine, Itabashi-ku, Tokoyo 173-8605, Japan.
Fumiaki
F
Saito
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;
Mary E
ME
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-campbell@uiowa.edu.
Kevin P
KP
Campbell
D000818:Animals; D064211:Connectin / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D049030:Dystroglycans / Q000378:metabolism*; D056966:Excitation Contraction Coupling / Q000187:drug effects; D005260:Female; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D009336:Necrosis; D009929:Organ Size; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism; D012518:Sarcomeres / Q000187:drug effects / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology
D064211:Connectin; D012333:RNA, Messenger; D013629:Tamoxifen; D049030:Dystroglycans
dystroglycan; eccentric contraction; muscular dystrophy; skeletal muscle; titin