Analysis Tools
mortality/aging
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• mice exhibit a short life span and die by 4 weeks of age
• early-onset cardiomyopathy and death are due to the combined consequences of impaired tRNA processing in both mitochondria and the nucleus
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growth/size/body
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• at 4 weeks of age, heart weight-to-body weight ratio is significantly higher than that in control mice
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• at 4 weeks of age, average body weight is significantly lower than that in control mice
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cardiovascular system
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• at 4 weeks of age, heart weight-to-body weight ratio is significantly higher than that in control mice
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• mice exhibit severe dilated cardiomyopathy, as determined by increased heart size, histology, and echocardiography
• in contrast, skeletal muscle shows no dramatic defects
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• mice show a significant decrease in fractional shortening (%) at 4 weeks of age
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• at 4 weeks of age, LVEDD (left ventricular end diastolic diameter) and LVESD (left ventricular end systolic diameter) are significantly increased whereas IVDS (intraventricular septum in diastole) and IVSS (intraventricular septum in systole) are significantly decreased relative to those in control mice
• however, LVDPW (left ventricular posterior wall in diastole), LVSPW (left ventricular posterior wall in systole) and heart rate remain relatively normal
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cellular
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• at 4 weeks of age, hearts show no significant changes in mitochondrial and nuclear DNA levels
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• impaired nuclear tRNA processing causes imbalanced levels of regulatory noncoding RNAs
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• heart mitochondria from 4-week-old mice show impaired 3 tRNA processing and severe mitochondrial dysfunction through impaired OXPHOS biogenesis and oxygen consumption
• loss of 3' tRNA processing results in impaired mitochondrial ribosome assembly
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• impaired OXPHOS biogenesis results in a significant reduction in mitochondrial oxygen consumption in the non-phosphorylated, phosphorylated, and uncoupled respiration state of all three proton-pumping complexes
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• heart mitochondria show a profound reduction in mitochondrial respiration at complex I, II-III, and IV relative to controls
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• heart mitochondria from 4-week-old mice show a significant reduction in protein synthesis of all mitochondrially encoded proteins
• reduced nuclear tRNA levels result in a ~50% reduction in cytoplasmic protein synthesis because of reduced polysome formation
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homeostasis/metabolism
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• heart mitochondria from 4-week-old mice show a significant reduction in protein synthesis of all mitochondrially encoded proteins
• reduced nuclear tRNA levels result in a ~50% reduction in cytoplasmic protein synthesis because of reduced polysome formation
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muscle
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• mice exhibit severe dilated cardiomyopathy, as determined by increased heart size, histology, and echocardiography
• in contrast, skeletal muscle shows no dramatic defects
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• mice show a significant decrease in fractional shortening (%) at 4 weeks of age
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