Mouse Genome Informatics
cx1
    Tg(Myh6-rtTA)8585Jam/0
Tg(tetO-Fgfr3*R248C/Fgfr1)#Dor/0

involves: 129 * C57BL/6 * FVB * FVB/NTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• progressively increasing myocyte size with DOX treatment
• cardiomyocyte cross-sectional area is increased by one week of DOX treatment and continues to increase through 6 months of DOX induction
• cardiomyocyte cross-sectional area is reduced by 24% after DOX removal but remains larger than controls
• patchy areas of myocyte disarray are seen after 42 days of DOX treatment
• following 42 days of DOX treatment, hearts are larger and this increase is even more apparent after 300 days of DOX treatment
• mice show progressive development of cardiac concentric hypertrophy with preservation of systolic function from baseline through 6 months of DOX induction
• mice exhibit an elevation of left ventricle mass index by one week of DOX induction
• after 10 months of DOX treatment, concentric hypertrophy is still present, without any progression to left ventricle dilatation
• both treatment with losartan and propranolol one week prior to the start of DOX and continued throughout one week of induction abrogate the hypertrophic response (left ventricle mass index) and moderately block the increase in left ventricle posterior wall thickness
• dynamic obstruction in the proximal left ventricle is seen with six weeks of DOX treatment
• mice exhibit an increase in left ventricle diastolic posterior wall thickness within one day of DOX induction; the wall thickness is concentric and symmetrical
• left ventricle diastolic posterior wall thickness is reduced by 16% after DOX removal, but remains elevated
• increase in interstitial fibrosis is seen after 42 days of DOX treatment
• end systolic volume and end diastolic volume are decreased within one day of DOX induction
• slope of the end systolic pressure-volume relationship is elevated within 24 hours of DOX induction
• ventricular myocytes treated with DOX for 1-2 days have shorter lengths at both diastole and systole, with an overall increase in fractional shortening, indicating impaired relaxation and enhanced contraction of cardiomyocytes
• in the absence of doxycycline (DOX), mice show a small, but significant, increase in left ventricle peak outflow velocity, however cardiac mass, myocyte size and left ventricle wall thickness are normal, indicating increased contractility but no hypertrophy at baseline
• mice show an increase in contractility following DOX treatment, as evidenced by an elevated slope of the end-systolic pressure-volume relationship between the baseline and increased afterload pressure-volume following constriction of the transverse aorta
• mice treated with DOX for six weeks show elevated late-peaking outflow velocities compared to non-DOX treated mice
• left ventricle peak outflow velocity measured at the point of flow convergence in the mid-ventricle decreases by 20% after DOX removal but remains elevated compared to controls
• treatment with propranolol one week prior to the start of DOX and continued throughout one week of induction reduces the dynamic obstruction as measured by left ventricle outflow velocity but not completely
• left ventricle internal diastolic diameter is decreased within one week of DOX induction
• left ventricle mass index and left ventricle internal diastolic diameter returns to near control levels after DOX removal
• treatment with DOX leads to hypertrophic cardiomyopathy

muscle
• progressively increasing myocyte size with DOX treatment
• cardiomyocyte cross-sectional area is increased by one week of DOX treatment and continues to increase through 6 months of DOX induction
• cardiomyocyte cross-sectional area is reduced by 24% after DOX removal but remains larger than controls
• in the absence of doxycycline (DOX), mice show a small, but significant, increase in left ventricle peak outflow velocity, however cardiac mass, myocyte size and left ventricle wall thickness are normal, indicating increased contractility but no hypertrophy at baseline
• mice show an increase in contractility following DOX treatment, as evidenced by an elevated slope of the end-systolic pressure-volume relationship between the baseline and increased afterload pressure-volume following constriction of the transverse aorta
• mice treated with DOX for six weeks show elevated late-peaking outflow velocities compared to non-DOX treated mice
• left ventricle peak outflow velocity measured at the point of flow convergence in the mid-ventricle decreases by 20% after DOX removal but remains elevated compared to controls
• treatment with propranolol one week prior to the start of DOX and continued throughout one week of induction reduces the dynamic obstruction as measured by left ventricle outflow velocity but not completely
• left ventricle internal diastolic diameter is decreased within one week of DOX induction
• left ventricle mass index and left ventricle internal diastolic diameter returns to near control levels after DOX removal
• treatment with DOX leads to hypertrophic cardiomyopathy

behavior/neurological
N
• mice fed DOX for 6 months show normal exercise tolerance (J:211151)


Mouse Genome Informatics
cx2
    Tg(Myh6-rtTA)8585Jam/0
Tg(tetO-CUGBP1)3413Coop/0

involves: FVB * FVB/N * FVB/NTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• following doxycycline treatment

cardiovascular system
• following doxycycline treatment for 8 days
• following doxycycline treatment
• following doxycycline treatment
• following doxycycline treatment, mice exhibit decreased posterior wall thickness during systole unlike in doxycycline-treated Tg(Myh6-rtTA)8585Jam mice
• following doxycycline treatment, mice exhibit increased left ventricular dilation with left ventricular internal diameter in diastole and systole compared with doxycycline-treated Tg(Myh6-rtTA)8585Jam mice
• following doxycycline treatment for 8 days, mice exhibit dilated cardiomyopathy with widespread degeneration, necrosis, and loss of myocardial fibers unlike doxycycline-treated Tg(Myh6-rtTA)8585Jam mice
• following doxycycline treatment for 7 to 8 days, mice exhibit reduced ejection fraction compared with doxycycline-treated Tg(Myh6-rtTA)8585Jam mice
• following doxycycline treatment
• following doxycycline treatment, QRS complex is prolonged compared to in doxycycline-treated Tg(Myh6-rtTA)8585Jam mice

behavior/neurological
• 7 days after doxycycline treatment

muscle
• following doxycycline treatment for 8 days, mice exhibit dilated cardiomyopathy with widespread degeneration, necrosis, and loss of myocardial fibers unlike doxycycline-treated Tg(Myh6-rtTA)8585Jam mice
• following doxycycline treatment for 7 to 8 days, mice exhibit reduced ejection fraction compared with doxycycline-treated Tg(Myh6-rtTA)8585Jam mice
• following doxycycline treatment for 8 days

Mouse Models of Human Disease
OMIM IDRef(s)
Myotonic Dystrophy 1; DM1 160900 J:157646


Mouse Genome Informatics
cx3
    Tg(Myh6-rtTA)8585Jam/0
Tg(tetO-Ppargc1a)1Dpk/0

involves: FVB * FVB/NTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• following doxycycline treatment of neonates, myofibril mitochondria density is increased 3.5-fold compared with wild-type myofibrils due to increased biogenesis
• doxycycline-treated adult mice exhibit an increased in mitochondrial biogenesis in myofibrils compared with wild-type mice but not to the extent observed in doxycycline treated neonates
• however, removal of doxycycline restores normal mitochondria
• following doxycycline treatment, adult mice exhibit eccentric hypertrophy unlike in wild-type mice
• 2 week after doxycycline treatment, adult mice exhibit increased end-diastolic and end-systolic left ventricle diameter and a mild increase in left ventricular wall thickness compared with wild-type mice
• following doxycycline treatment of adult mice
• following doxycycline treatment of adult mice
• following doxycycline treatment, adult mice exhibit decreased fractional shortening compared with wild-type mice
• however, removal of doxycycline restores cardiac muscle contractility
• following doxycycline treatment of adult mice
• following removal of doxycycline
• however, no increase in cardiac cell apoptosis is observed
• following induction of expression with doxycycline, adult mice exhibit reversible cardiomyopathy unlike wild-type mice

cellular
• following doxycycline treatment, adult mice exhibit an increase in mitochondrial number along with mitochondrial ultrastructural abnormalities unlike in wild-type mice
• following doxycycline treatment of neonates, myofibril mitochondria density is increased 3.5-fold compared with wild-type myofibrils due to increased biogenesis
• doxycycline-treated adult mice exhibit an increased in mitochondrial biogenesis in myofibrils compared with wild-type mice but not to the extent observed in doxycycline treated neonates
• however, removal of doxycycline restores normal mitochondria

muscle
• following doxycycline treatment of neonates, myofibril mitochondria density is increased 3.5-fold compared with wild-type myofibrils due to increased biogenesis
• doxycycline-treated adult mice exhibit an increased in mitochondrial biogenesis in myofibrils compared with wild-type mice but not to the extent observed in doxycycline treated neonates
• however, removal of doxycycline restores normal mitochondria
• following doxycycline treatment, adult mice exhibit decreased fractional shortening compared with wild-type mice
• however, removal of doxycycline restores cardiac muscle contractility
• following induction of expression with doxycycline, adult mice exhibit reversible cardiomyopathy unlike wild-type mice
• however, no increase in cardiac cell apoptosis is observed