Analysis Tools
mortality/aging
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• no mice survive past P24
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• although born phenotypically normal and at the expected Mendelian ratios, mice begin to die from P13 often of sudden death
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cardiovascular system
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• at P10, mice exhibit mild F-actin accumulations in the myocardium relative to wild-type controls
• large amounts of F-actin accumulations are noted at P12, with further increases at P14
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• at P12, mutant myofibrils show severe disruption of the sarcomeric structure; the sarcomeric structural component alpha-actinin and the F-actin pointed end capping protein Tmod1 are not aligned in a striated pattern in regions with strong F-actin accumulations, unlike in control mice
• within actin aggregates, sarcomeric alpha-actinin staining is strongly reduced and Tmod1 staining is diffused but robust
• at P12, TEM analysis of mutant cardiac muscle showed a normal looking structure, with distinct A bands and narrow and uniformly spaced Z lines, and no evidence of nemaline bodies; however, strong F-actin accumulations were found in areas of myofibrillar disruption
• Western blotting analysis showed increased cardiac levels of sarcomeric proteins (Tmod1, cardiac troponin T, cardiac troponin I, tropomyosin, pan-actin), and total cofilin, but not of sarcomeric alpha-actinin
• total cofilin is abundant in myofibrils where F-actin accumulations are present
• at P10, qPCR analysis revealed that mRNA expression levels of alpha-skeletal muscle actin and aortic smooth muscle actin are significantly increased and those of alpha-cardiac muscle actin-1 are decreased
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• starting at P12, mutant cardiomyocytes are significantly larger, indicating hypertrophic growth of cardiomyocytes
• however, no significant changes in cell proliferation and apoptosis are observed, as shown by Ki-67 and TUNEL staining
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• interventricular septum in diastole begins to increase at P10
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• starting at P12, mice exhibit a larger heart than control mice
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• starting at P12, mice show a significant increase in heart weight/body weight ratio relative to control mice
• however, body weight remains normal from birth to death
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• at P12, mutant hearts show markedly increased mRNA levels of the hypertrophic markers ANP and BNP, unlike control hearts
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• left ventricular internal dimension in diastole begins to decrease at P10
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• at P12, mutant hearts exhibit a significantly decreased LV fractional shortening (FS) and LV ejection fraction (EF) relative to control hearts
• EF, FS and left ventricular internal dimension in diastole begin to decrease and interventricular septum in diastole begins to increase at P10
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• at P10, mice show a significant decrease in heart rate (417 +/- 11 bpm) relative to controls (447 +/- 19 bpm)
• at P12, the heart rate is further reduced (383 +/- 39 bpm) relative to controls (453 +/- 58 bpm)
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• mice exhibit alterations in the QT interval, ST height, and T-wave amplitude indicating abnormalities of ventricular electrocardiographic repolarization
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• starting at P10, mice display prolonged P duration relative to control mice
• however, no differences are detected in the PR interval or QRS waves at P10 and P12
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• starting at P12, mice display a prolonged QT interval relative to control mice
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• starting at P12, mice display an elevated ST height relative to control mice
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• starting at P10, mice show a significant increase in T-wave amplitude relative to control mice
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muscle
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• at P10, mice exhibit mild F-actin accumulations in the myocardium relative to wild-type controls
• large amounts of F-actin accumulations are noted at P12, with further increases at P14
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• at P12, mutant myofibrils show severe disruption of the sarcomeric structure; the sarcomeric structural component alpha-actinin and the F-actin pointed end capping protein Tmod1 are not aligned in a striated pattern in regions with strong F-actin accumulations, unlike in control mice
• within actin aggregates, sarcomeric alpha-actinin staining is strongly reduced and Tmod1 staining is diffused but robust
• at P12, TEM analysis of mutant cardiac muscle showed a normal looking structure, with distinct A bands and narrow and uniformly spaced Z lines, and no evidence of nemaline bodies; however, strong F-actin accumulations were found in areas of myofibrillar disruption
• Western blotting analysis showed increased cardiac levels of sarcomeric proteins (Tmod1, cardiac troponin T, cardiac troponin I, tropomyosin, pan-actin), and total cofilin, but not of sarcomeric alpha-actinin
• total cofilin is abundant in myofibrils where F-actin accumulations are present
• at P10, qPCR analysis revealed that mRNA expression levels of alpha-skeletal muscle actin and aortic smooth muscle actin are significantly increased and those of alpha-cardiac muscle actin-1 are decreased
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• starting at P12, mutant cardiomyocytes are significantly larger, indicating hypertrophic growth of cardiomyocytes
• however, no significant changes in cell proliferation and apoptosis are observed, as shown by Ki-67 and TUNEL staining
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• at P12, mutant hearts exhibit a significantly decreased LV fractional shortening (FS) and LV ejection fraction (EF) relative to control hearts
• EF, FS and left ventricular internal dimension in diastole begin to decrease and interventricular septum in diastole begins to increase at P10
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growth/size/body
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• starting at P12, mice exhibit a larger heart than control mice
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• starting at P12, mice show a significant increase in heart weight/body weight ratio relative to control mice
• however, body weight remains normal from birth to death
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• at P12, mutant hearts show markedly increased mRNA levels of the hypertrophic markers ANP and BNP, unlike control hearts
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