Molecular and cellular contractile dysfunction of dystrophic muscle from young mice.
The purpose of this study was to determine whether contractile protein alterations are responsible for force deficits in young dystrophic muscle. Contractility of intact extensor digitorum longus muscles and permeabilized fibers from wild-type (wt), dystrophin-deficient (mdx), and dystrophin/utrophin-deficient (mdx:utrn-/-) mice aged 21 and 35 days was determined. Myosin structural dynamics were assessed by site-directed spin labeling and electron paramagnetic resonance spectroscopy. The principal finding was that force generation was depressed by approximately 20% in mdx muscles, but fiber Ca2+-activated force and myosin structure were not different from wt animals, suggesting that contractile proteins are not responsible for the force deficits in those muscles. For mdx:utrn-/- mice, muscle and fiber forces were approximately 40% lower than wt and the fraction of strong-binding myosin during contraction was reduced by 13%. These data indicate that contractile protein alterations, in addition to myosin dysfunction, cause force deficit in muscles from young mdx:utrn-/- mice. Elucidating the molecular mechanisms underlying muscle weakness at the onset of disease is important for designing treatment strategies.
Lowe
Dawn A
DA
Department of Biochemistry, Molecular Biology Biophysics, University of Minnesota, 420 Delaware Street SE, MMC 388, Minneapolis, Minnesota 55455, USA. lowex017@umn.edu
Williams
Brian O
BO
Thomas
David D
DD
Grange
Robert W
RW
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D015992:Body Mass Index; D003285:Contractile Proteins / Q000378:metabolism; D016189:Dystrophin / Q000172:deficiency; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000502:physiology*; D018482:Muscle, Skeletal / Q000473:pathology* / Q000503:physiopathology*; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009218:Myosins / Q000378:metabolism; D049411:Utrophin / Q000172:deficiency
D003285:Contractile Proteins; D016189:Dystrophin; D049411:Utrophin; D009218:Myosins