Independent variability of microtubule perturbations associated with dystrophinopathy.
Absence of the protein dystrophin causes Duchenne muscular dystrophy. Dystrophin directly binds to microtubules in vitro, and its absence in vivo correlates with disorganization of the subsarcolemmal microtubule lattice, increased detyrosination of α-tubulin, and altered redox signaling. We previously demonstrated that the dystrophin homologue utrophin neither binds microtubules in vitro nor rescues microtubule lattice organization when overexpressed in muscles of dystrophin-deficient mdx mice. Here, we fine-mapped the dystrophin domain necessary for microtubule binding to spectrin-like repeats 20–22. We show that transgenic mdx mice expressing a full-length dystrophin/utrophin chimera completely lacking microtubule binding activity are surprisingly rescued for all measured dystrophic phenotypes, including full restoration of microtubule lattice organization. Conversely, despite the presence of dystrophin at the sarcolemma, β-sarcoglycan-deficient skeletal muscle presents with a disorganized and densified microtubule lattice. Finally, we show that the levels of α-tubulin detyrosination remain significantly elevated to that of mdx levels in transgenic mdx mice expressing nearly full-length dystrophin. Our results demonstrate that the microtubule-associated perturbations of mdx muscle are distinct, separable, and can vary independently from other parameters previously ascribed to dystrophin deficiency.
Department of Biochemistry, Molecular Biology, and Biophysics, and Program in Molecular, Cellular, Developmental Biology, and Genetics, University of Minnesota - Twin Cities, Minneapolis, MN, USA.
Joseph J
JJ
Belanto
Department of Biochemistry, Molecular Biology, and Biophysics, and Program in Molecular, Cellular, Developmental Biology, and Genetics, University of Minnesota - Twin Cities, Minneapolis, MN, USA.
John T
JT
Olthoff
Programs in Rehabilitation Science and Physical Therapy, Department of Physical Medicine and Rehabilitation, University of Minnesota - Twin Cities, Minneapolis, MN, USA.
Tara L
TL
Mader
Department of Biochemistry, Molecular Biology, and Biophysics, and Program in Molecular, Cellular, Developmental Biology, and Genetics, University of Minnesota - Twin Cities, Minneapolis, MN, USA.
Christopher M
CM
Chamberlain
Department of Biochemistry, Molecular Biology, and Biophysics, and Program in Molecular, Cellular, Developmental Biology, and Genetics, University of Minnesota - Twin Cities, Minneapolis, MN, USA.
D'anna M
DM
Nelson
Department of Biochemistry, Molecular Biology, and Biophysics, and Program in Molecular, Cellular, Developmental Biology, and Genetics, University of Minnesota - Twin Cities, Minneapolis, MN, USA.
Preston M
PM
McCourt
Department of Biochemistry, Molecular Biology, and Biophysics, and Program in Molecular, Cellular, Developmental Biology, and Genetics, University of Minnesota - Twin Cities, Minneapolis, MN, USA.
Dana M
DM
Talsness
Department of Pathology & Cell Biology, Columbia University, New York, NY, USA.
Gregg G
GG
Gundersen
Programs in Rehabilitation Science and Physical Therapy, Department of Physical Medicine and Rehabilitation, University of Minnesota - Twin Cities, Minneapolis, MN, USA.
Dawn A
DA
Lowe
Department of Biochemistry, Molecular Biology, and Biophysics, and Program in Molecular, Cellular, Developmental Biology, and Genetics, University of Minnesota - Twin Cities, Minneapolis, MN, USA.
James M
JM
Ervasti
D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009137:Muscular Dystrophy, Animal / Q000235:genetics; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D000072417:Protein Domains / Q000235:genetics; D049031:Sarcoglycans / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D049411:Utrophin / Q000378:metabolism*
D003598:Cytoskeletal Proteins; D016189:Dystrophin; D008565:Membrane Proteins; D049031:Sarcoglycans; D014404:Tubulin; D049411:Utrophin