Microarchitecture Is Severely Compromised but Motor Protein Function Is Preserved in Dystrophic mdx Skeletal Muscle

Progressive force loss in Duchenne muscular dystrophy is characterized by degeneration/regeneration cycles and fibrosis. Disease progression may involve structural remodeling of muscle tissue. An effect on molecular motorprotein function may also be possible. We used second harmonic generation imagi...

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Bibliographic Details
Published in:	Biophysical journal Vol. 98; no. 4; pp. 606 - 616
Main Authors:	Friedrich, O., Both, M., Weber, C., Schürmann, S., Teichmann, M.D.H., von Wegner, F., Fink, R.H.A., Vogel, M., Chamberlain, J.S., Garbe, C.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 17-02-2010 Biophysical Society The Biophysical Society
Subjects:	Activation Aging Algorithms Animals Biomechanical Phenomena Biophysics Deviation Dystrophin - metabolism Fibers Gene Expression Regulation Gene therapy Humans Imaging Imaging, Three-Dimensional Irregularities Mice Mice, Inbred mdx Mice, Transgenic Microscopy Molecular Imaging Molecular Motor Proteins - chemistry Molecular Motor Proteins - metabolism Movement Muscle Fibers, Skeletal - metabolism Muscle, Motility, and Motor Proteins Muscle, Skeletal - metabolism Muscle, Skeletal - pathology Muscle, Skeletal - physiology Muscles Muscular Dystrophies - metabolism Muscular Dystrophies - physiopathology Muscular dystrophy Musculoskeletal system Proteins Sarcomeres - metabolism Second harmonic generation
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Summary:	Progressive force loss in Duchenne muscular dystrophy is characterized by degeneration/regeneration cycles and fibrosis. Disease progression may involve structural remodeling of muscle tissue. An effect on molecular motorprotein function may also be possible. We used second harmonic generation imaging to reveal vastly altered subcellular sarcomere microarchitecture in intact single dystrophic mdx muscle cells (∼1 year old). Myofibril tilting, twisting, and local axis deviations explain at least up to 20% of force drop during unsynchronized contractile activation as judged from cosine angle sums of myofibril orientations within mdx fibers. In contrast, in vitro motility assays showed unaltered sliding velocities of single mdx fiber myosin extracts. Closer quantification of the microarchitecture revealed that dystrophic fibers had significantly more Y-shaped sarcomere irregularities (“verniers”) than wild-type fibers (∼130/1000 μm 3 vs. ∼36/1000 μm 3). In transgenic mini-dystrophin-expressing fibers, ultrastructure was restored (∼38/1000 μm 3 counts). We suggest that in aged dystrophic toe muscle, progressive force loss is reflected by a vastly deranged micromorphology that prevents a coordinated and aligned contraction. Second harmonic generation imaging may soon be available in routine clinical diagnostics, and in this work we provide valuable imaging tools to track and quantify ultrastructural worsening in Duchenne muscular dystrophy, and to judge the beneficial effects of possible drug or gene therapies.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0006-3495 1542-0086
DOI:	10.1016/j.bpj.2009.11.005