Analysis Tools
mortality/aging
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• few males survive to weaning and ~70% of these survivors die suddenly between 5 and 10 weeks of age
• only ~30% of males survive to adulthood
• however, females survive about as long as wild-type mice
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• ~70% of males that survive to weaning die suddenly within 12 weeks of birth while only 5.4% of females die by that age
• males are prone to sudden death without any other obvious signs of distress
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• of 115 pups born from heterozygous crosses, only 5.3% of males survive to weaning (~3 weeks) versus 16.9% of females, indicating a sex bias in survival at young ages
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growth/size/body
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• at P21, both sexes exhibit significantly lower body weights than heterozygous or wild-type controls
• in males, body weight is significantly reduced as early as P3
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• both sexes show normal birth weights but grow at significantly slower rates than heterozygous or wild-type controls; this trend is more pronounced in males
• however, DEXA analysis of males revealed no differences in bone mineral content, lean muscle or fat content at 11 weeks of age
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cardiovascular system
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• at 55 weeks of age, males show a significant increase in left ventricular internal dimension during systole (LVIDs/BW) relative to wild-type controls
• however, no significant differences in left ventricular chamber size, function and wall thickness are noted in males at 10 or 21 weeks of age, or in females at 9-109 weeks of age relative to age-matched controls
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• fibrosis, when observed, is not present until ~12 months of age
• 1 of 3 adult males analyzed showed abundant interstitial fibrosis separating and replacing the cardiomyocytes throughout the myocardium; a more modest interstitial fibrosis was noted in a second male
• however, none of the 4 females analyzed displayed cardiac fibrosis
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• surviving males develop dilated cardiomyopathy after 6 months of age
• 1 of 3 adult males analyzed showed a modest increase in right and left ventricular chamber size with abundant interstitial fibrosis
• older males exhibit signs of mild chamber dilatation
• dilated cardiomyopathy is more pronounced in males versus females
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• at 55 weeks of age, males show a significant decrease in left ventricular ejection fraction, LVEF (%), relative to wild-type controls
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• older mice show defects in both the suprahisian conduction system (prolonged AV Wenckebach cycle length) and the infranodal conduction system (prolonged HV-intervals)
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• older mice show a significant increase in the HV-interval relative to control mice
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• both males and females exhibit increased QRS duration as they age
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• both males and females exhibit a prolonged QT interval as they age; however, the rate corrected QT-intervals are not significantly different from those in controls
• all ECG parameters are normal in males and females at ~30-weeks of age or earlier
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• one male with extensive myocardial fibrosis showed increased ANP staining in the left ventricle
• a strong cardiac ankyrin repeat protein (CARP) signal was detected in 3 of 3 males, but only in 1 of 3 females
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vision/eye
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• almost all males and ~50% of females are prone to eye inflammation and infections
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small pupil
(
J:234044
)
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• males exhibit significantly decreased pupil diameters, suggesting microphthalmia
• however, no visual defects are detected by electroretinography or pupillometry
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• microphthalmia is seen predominantly in males
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immune system
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• almost all males and ~50% of females are prone to eye inflammation and infections
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• almost all males and ~50% of females are prone to eye inflammation and infections
• eye infections typically appear at ~6 weeks of age and are more common in the right eye than the left eye
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homeostasis/metabolism
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• homozygotes display normal glucose tolerance and treadmill parameters (including VO2, VCO2, respiratory exchange ratio, and heat generated)
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• when subjected to treadmill exercise tests, older males travel about half as far and do less work than wild-type controls
• in contrast, females perform as well as wild-type controls in the treadmill test
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behavior/neurological
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• homozygotes are weaker in grip strength assays, probably as a result of smaller size
• no ultrastructural abnormalities are noted in isolated EDL muscles
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• when subjected to treadmill exercise tests, older males travel about half as far and do less work than wild-type controls
• in contrast, females perform as well as wild-type controls in the treadmill test
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muscle
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• surviving males develop dilated cardiomyopathy after 6 months of age
• 1 of 3 adult males analyzed showed a modest increase in right and left ventricular chamber size with abundant interstitial fibrosis
• older males exhibit signs of mild chamber dilatation
• dilated cardiomyopathy is more pronounced in males versus females
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• at 55 weeks of age, males show a significant decrease in left ventricular ejection fraction, LVEF (%), relative to wild-type controls
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cellular
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• fibrosis, when observed, is not present until ~12 months of age
• 1 of 3 adult males analyzed showed abundant interstitial fibrosis separating and replacing the cardiomyocytes throughout the myocardium; a more modest interstitial fibrosis was noted in a second male
• however, none of the 4 females analyzed displayed cardiac fibrosis
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