Phenotypes Associated with This Genotype

Genotype
MGI:5810170

• Allelic Composition: Mtor^tm1.1Gcon/Mtor^tm1.1Gcon; A1cf^{Tg(Myh6-cre/Esr1*)1Jmk}/A1cf⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * FVB/N

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

Enlarged hearts with thinned ventricular walls and enlarged cardiac chambers in Mtor^tm1.1Gcon/Mtor^tm1.1Gcon A1cf^{Tg(Myh6-cre/Esr1*)1Jmk}/0 mice

mortality/aging

premature death ( J:163763 )

♂ • mice start dying at 4 weeks after tamoxifen (TMX) administration; the median survival age is 6 weeks and no mice survive for >8 weeks

growth/size/body

enlarged heart ( J:163763 )

♂ • at 4 weeks after TMX treatment, mice exhibit significantly enlarged hearts relative to controls

cardiovascular system

abnormal myocardial fiber morphology ( J:163763 )

♂ • at 2 weeks after TMX treatment, LV myocardium exhibits sarcomeric disarray and swollen mitochondria, unlike in control hearts

decreased myocardial fiber size ( J:163763 )

♂ • at 2 weeks after TMX treatment, cross-sectional area of cardiomyocytes is reduced relative to that in control mice

♂ • adult cardiomyocytes isolated from TMX-treated mice are significantly thinner and shorter than those of control mice

increased heart atrium size ( J:163763 )

♂ • atrial chambers are enlarged at 4 weeks after TMX treatment

thin interventricular septum ( J:163763 )

♂ • interventricular septum is thinner than normal at 4 weeks after TMX treatment

enlarged heart ( J:163763 )

♂ • at 4 weeks after TMX treatment, mice exhibit significantly enlarged hearts relative to controls

decreased heart left ventricle wall thickness ( J:163763 )

♂ • left ventricle (LV) wall is thinner than normal at 4 weeks after TMX treatment

increased heart ventricle size ( J:163763 )

♂ • ventricular chambers are enlarged at 4 weeks after TMX treatment

cardiac interstitial fibrosis ( J:163763 )

♂ • at 4 weeks after TMX treatment, mice show increased interstitial fibrosis in the LV and interventricular septum relative to controls

♂ • the cardiac fibrotic index is already increased at 1 week after TMX treatment and becomes significantly increased thereafter

dilated cardiomyopathy ( J:163763 )

♂ • TMX-treated mice develop lethal dilated cardiomyopathy

decreased cardiac muscle contractility ( J:163763 )

♂ • TMX-treated mice show markedly lower basal inotropy and lusitropy and only very weak reactivity to stimulation with increasing units of dobutamine

decreased heart ventricle muscle contractility ( J:163763 )

♂ • at 4 weeks after TMX treatment, LV fractional shortening percentage (LVFS %) is significantly reduced relative to that in controls

abnormal myocardial fiber physiology ( J:163763 )

♂ • in culture, adult ventricular myocytes isolated from TMX-treated mice show significantly reduced protein synthesis relative to controls, as assessed by a [³H]leucine uptake assay

♂ • TMX-treated mice show a progressive (2- to 8-fold) increase in the expression of cardiac fetal genes (Nppa, Myh7, Acta1) relative to controls at 2 weeks and 4 weeks post-TMX

♂ • TMX-treated mice show a progressive reduction in cytochrome c oxidase subunit IV (CoxIV) expression, indicating a loss in the oxidative capacity of myocardial mitochondria

increased response of heart to induced stress ( J:163763 )

♂ • at 2 weeks after transverse aortic constriction (TAC), i.e. 3 weeks post-TMX treatment, mice show an impaired hypertrophic response and accelerated heart failure progression, as determined by a significantly reduced increase in LV wall thickness, a more dilated LV chamber, a significantly reduced ratio of LV weight- and heart weight-to-tibial length, accelerated contractile dysfunction, reduced induction of cardiac fetal genes, and significantly reduced survival relative to control TAC mice, with a 40% death rate already noted after 1 week of TAC

congestive heart failure ( J:163763 )

♂ • at 4 weeks after TMX treatment, mice exhibit heart failure, as assessed by echocardiography and the dobutamine stress test

♂ • however, cardiac function is maintained up to 2-3 weeks after TMX treatment

cellular

cardiac interstitial fibrosis ( J:163763 )

♂ • at 4 weeks after TMX treatment, mice show increased interstitial fibrosis in the LV and interventricular septum relative to controls

♂ • the cardiac fibrotic index is already increased at 1 week after TMX treatment and becomes significantly increased thereafter

dilated mitochondrion ( J:163763 )

♂ • at 2 weeks after TMX treatment, LV myocardium exhibits swollen mitochondria, unlike in control hearts

abnormal autophagy ( J:163763 )

♂ • at 1 week after TMX treatment, cardiac expression of several autophagy-related proteins is increased and autophagic bodies are observed in the myocardium, unlike in control hearts

increased cardiomyocyte apoptosis ( J:163763 )

♂ • TMX-treated mice show a progressive and severe loss of cardiomyocytes due to apoptosis, as shown by TUNEL staining

♂ • at 4 weeks after TMX treatment, cleaved Parp expression is significantly increased in the heart relative to that in control mice

abnormal mitochondrial physiology ( J:163763 )

♂ • TMX-treated mice show a progressive reduction in cytochrome c oxidase subunit IV (CoxIV) expression, indicating reduced oxidative capacity of myocardial mitochondria

abnormal translation ( J:163763 )

♂ • in culture, adult ventricular myocytes isolated from TMX-treated mice show significantly reduced protein synthesis relative to controls, as assessed by a [³H]leucine uptake assay

homeostasis/metabolism

increased response of heart to induced stress ( J:163763 )

♂ • at 2 weeks after transverse aortic constriction (TAC), i.e. 3 weeks post-TMX treatment, mice show an impaired hypertrophic response and accelerated heart failure progression, as determined by a significantly reduced increase in LV wall thickness, a more dilated LV chamber, a significantly reduced ratio of LV weight- and heart weight-to-tibial length, accelerated contractile dysfunction, reduced induction of cardiac fetal genes, and significantly reduced survival relative to control TAC mice, with a 40% death rate already noted after 1 week of TAC

abnormal autophagy ( J:163763 )

♂ • at 1 week after TMX treatment, cardiac expression of several autophagy-related proteins is increased and autophagic bodies are observed in the myocardium, unlike in control hearts

abnormal translation ( J:163763 )

♂ • in culture, adult ventricular myocytes isolated from TMX-treated mice show significantly reduced protein synthesis relative to controls, as assessed by a [³H]leucine uptake assay

ascites ( J:163763 )

♂ • TMX-treated mice develop ascites

pleural effusion ( J:163763 )

♂ • TMX-treated mice exhibit pleural effusions

muscle

abnormal myocardial fiber morphology ( J:163763 )

♂ • at 2 weeks after TMX treatment, LV myocardium exhibits sarcomeric disarray and swollen mitochondria, unlike in control hearts

decreased myocardial fiber size ( J:163763 )

♂ • at 2 weeks after TMX treatment, cross-sectional area of cardiomyocytes is reduced relative to that in control mice

♂ • adult cardiomyocytes isolated from TMX-treated mice are significantly thinner and shorter than those of control mice

dilated cardiomyopathy ( J:163763 )

♂ • TMX-treated mice develop lethal dilated cardiomyopathy

decreased cardiac muscle contractility ( J:163763 )

♂ • TMX-treated mice show markedly lower basal inotropy and lusitropy and only very weak reactivity to stimulation with increasing units of dobutamine

decreased heart ventricle muscle contractility ( J:163763 )

♂ • at 4 weeks after TMX treatment, LV fractional shortening percentage (LVFS %) is significantly reduced relative to that in controls

increased cardiomyocyte apoptosis ( J:163763 )

♂ • TMX-treated mice show a progressive and severe loss of cardiomyocytes due to apoptosis, as shown by TUNEL staining

♂ • at 4 weeks after TMX treatment, cleaved Parp expression is significantly increased in the heart relative to that in control mice

abnormal sarcomere morphology ( J:163763 )

♂ • at 2 weeks after TMX treatment, LV myocardium exhibits sarcomeric disarray, unlike in control hearts

respiratory system

pleural effusion ( J:163763 )

♂ • TMX-treated mice exhibit pleural effusions