Analysis Tools
muscle
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• ultrastructurally, affected sternomastoid muscles exhibit loss of sarcomeric organization and abnormal mitochondria
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absent Z line
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J:33714
)
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• ultrastructurally, affected sternomastoid muscles exhibit focal loss of Z lines
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• ultrastructurally, affected sternomastoid muscles exhibit dilation of the sarcoplasmic reticulum
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• at 7-11 months, sternomastoid muscles from older (but not younger) homozygote exhibit increased variability in fiber size, with the mean fiber area ranging from 0.7 to 1.5 that of wild-type mice; no significant differences are noted in fiber type distribution or fiber total number
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• in vitro, sternomastoid muscles from young (3- to 4-mo-old) homozygotes show no significant differences in isometric twitch or tetanic force, contraction or relaxation times relative to wild-type muscles
• in contrast, sternomastoid muscles from older (7- to 11-mo-old) homozygotes show a 30%-50% reduction in twitch and tetanic force generation relative to wild-type muscles
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• homozygotes exhibit a progressive increase in skeletal muscle regenerative activity, as shown by a 3-4-fold increase of MyoD levels in neck, fore- and hindlimb muscles from 7- to 11-mo-old (but not younger) mutants relative to wild-type mice
• consistent with increased MyoD levels, a large proportion of fibers (1%) in sternomastoid muscles from older homozygotes express embryonic MHC vs only 0.4% of fibers in wild-type muscles, suggesting an increased incidence of muscle fiber regeneration over time
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• homozygotes exhibit progressive muscle weakness in the absence of a generalized neuropathy, neuromuscular junction transmission defects, abnormal neuromuscular innervation or reduced muscle fiber membrane electrical excitability
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• homozygotes display late-onset, progressive degenerative changes in skeletal muscle, including variation in fiber diameter, increased foci of degeneration/regeneration and increased fibrosis; no myotonia is ever observed
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cardiovascular system
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• adult homozygotes display distinct atrioventricular conduction abnormalities in the presence of normal intrinsic sinus node function
• no increased fibrosis, atrophy or altered cardiac function, chamber dimensions, wall thickness, or ventricular shortening are observed
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• adult homozygotes exhibit delayed atrioventricular (A-V) conduction, manifest as first-degree (10 of 10), second-degree (5 of 17), and third-degree (2 of 17) atrioventricular block
• on ECGs, all adult homozygotes exhibit a prolonged mean P-R interval of 48 7 ms (first-degree A-V block) vs 34 5 ms in wild-type mice; in contrast, basal heart rate, P-wave duration and other ECG intervals (QRS, J-T, Q-T) remain unaffected
• a trend towards an increase in P-R intervals is noted with age, such that P-R intervals of >50 ms are not observed at 6 months, and become apparent only at 16-17 months of age
• second- and third-degree heart block occurs at a higher frequency in 16-17-month-olds and primarily in mice with a P-R interval greater than or equal to 45 ms
• no further progression of higher-grade A-V block is noted during rest, ambulation, or graded exercise testing
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• left ventricle SR vesicles from 12-week-old male homozygotes show a ~2-fold decrease in phospholamban phosphorylation activity, as commonly found in acquired forms of heart failure
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homeostasis/metabolism
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• mutant ventricular homogenates exhibit significantly reduced Ca2+ uptake in cardiomyocyte sarcoplasmic reticulum (SR), with a 48% and 84% decrease at 200 and 20 nM free calcium concentrations, respectively, relative to wild-type
• reduced SR Ca2+ uptake is detected at 14 weeks of age i.e. prior to the first detectable signs of muscle weakness observed at 7-10 months
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| myotonic dystrophy type 1 | DOID:11722 |
OMIM:160900 |
J:33714 , J:53077 | |
