Phenotypes Associated with This Genotype

Genotype
MGI:7616527

• Allelic Composition: Atp6v0d1^em1Nju/Atp6v0d1^em1Nju; Tg(Adipoq-cre)1Evdr/0
• Genetic Background: involves: FVB/NJ

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

adipose tissue

decreased brown adipose tissue amount ( J:346448 )

• brown adipose tissue weight is reduced at 24 weeks of age

decreased total body fat amount ( J:346448 )

• mice exhibit diminished adipose depots at both 8 and 24 weeks of age

decreased epididymal fat pad weight ( J:346448 )

• at 24 weeks of age, mice have no visible epididymal white adipose depots

decreased inguinal fat pad weight ( J:346448 )

• inguinal white adipose tissue weight is largely reduced at both 8 and 24 weeks of age

decreased retroperitoneal fat pad weight ( J:346448 )

• at 24 weeks of age, mice have no visible retroperitoneal white adipose depots

lipodystrophy ( J:346448 )

• mice exhibit reduced and diminished adipose depots at 8 and 24 weeks of age, respectively

cardiovascular system

abnormal heart morphology ( J:346448 )

• excessive lipid accumulation is seen in the heart

increased myocardial fiber size ( J:346448 )

• increase in size of cardiomyocytes

• mice injected with AAV9-cTNT-myocardin at 16 weeks of age show reduced cardiomyocyte size

enlarged heart ( J:346448 )

• hearts are visibly larger in 36-week-old mice and the heart weight to tibia length ratio is increased

• however, no difference in the heart weight to body weight ratio is seen but this may be due to increase in liver weight

• mice injected with AAV9-cTNT-myocardin at 16 weeks of age show attenuation of the increased heart weight to tibial weight ratio

cardiac hypertrophy ( J:346448 )

• mice develop cardiac hypertrophy with preserved contractile function by 24 weeks of age but by 28 weeks of age, mice show apparent cardiac contractile dysfunction

• mice injected with AAV9-cTNT-myocardin show amelioration of cardiac hypertrophy but it is not completely corrected

• cardiac hypertrophy is not accompanied by activation of fetal genes, Nppa and Myh7, even when contractile function is impaired

cardiac fibrosis ( J:346448 )

• mice exhibit cardiac fibrosis

• mice injected with an adeno-associated virus 9 that expresses myocardin under the control of the Tnnt2 promoter (AAV9-cTNT-myocardin) at 16 weeks of age show reduced cardiac fibrosis

abnormal cardiovascular system physiology ( J:346448 )

• mice develop cardiac insulin resistance as indicated by decreased insulin receptor substrate (IRS)-1 and IRS-2 expression in hearts

• expression of genes associated with fatty acid uptake and oxidation is upregulated indicating that energy expenditure is reprogrammed in hearts so that is it is shifted preferentially to fatty acid oxidation

• while basal oxygen consumption rate of isolated cardiomyocytes is normal, FCCP (Trifluoromethoxy carbonylcyanide phenylhydrazone)-induced maximal respiration of isolated cardiomyocytes is reduced, despite comparable abundance of the mitochondrial respiratory complexes in hearts

• following application of etomoxir, an inhibitor for carnitine palmitoyl-transferase (CPT1), the reduction in FCCP-induced maximal respiration is greater in cardiomyocytes than in controls

• treatment with Rosiglitazone, a systemic insulin sensitizer, improves cardiac metabolism and function

decreased cardiac muscle contractility ( J:346448 )

• at 28 weeks of age, percent ejection fraction and percent fractional shortening are reduced by 59.4% and 31.2%, respectively, compared to 84.3% and 52.6% in controls and there is only a minor decrease in percent ejection fraction and percent fractional shorting in mice aged 36 weeks compared to those at 26 week of age, indicating slow progression of congestive heart failure

• mice injected with AAV9-cTNT-myocardin at 16 weeks of age increases percent ejection fraction and percent fractional shortening to levels comparable to controls

• treatment with Rosiglitazone, a systemic insulin sensitizer, improves cardiac metabolism and function

abnormal heart echocardiography feature ( J:346448 )

• echocardiography shows that the anterior and posterior wall thickness of the left ventricle at systole and diastole are larger, the internal left ventricle diameter at diastole is smaller at 12 weeks of age, but not 8 weeks of age, and the percent ejection fraction and fractional shortening are comparable to controls until 24 weeks and reduced at 28 weeks of age

growth/size/body

growth/size/body region phenotype ( J:346448 )

N • body weight is unaltered

enlarged heart ( J:346448 )

• hearts are visibly larger in 36-week-old mice and the heart weight to tibia length ratio is increased

• however, no difference in the heart weight to body weight ratio is seen but this may be due to increase in liver weight

• mice injected with AAV9-cTNT-myocardin at 16 weeks of age show attenuation of the increased heart weight to tibial weight ratio

cardiac hypertrophy ( J:346448 )

• mice develop cardiac hypertrophy with preserved contractile function by 24 weeks of age but by 28 weeks of age, mice show apparent cardiac contractile dysfunction

• mice injected with AAV9-cTNT-myocardin show amelioration of cardiac hypertrophy but it is not completely corrected

• cardiac hypertrophy is not accompanied by activation of fetal genes, Nppa and Myh7, even when contractile function is impaired

increased liver weight ( J:346448 )

homeostasis/metabolism

decreased circulating leptin level ( J:346448 )

• plasma leptin levels are reduced at 24 weeks of age

increased circulating cholesterol level ( J:346448 )

• plasma cholesterol levels are increased at 24 weeks of age and plasma cholesterol remains high at 36 weeks of age

increased circulating free fatty acids level ( J:346448 )

• non-esterified fatty acid (NEFA) levels are high at 36 weeks of age

decreased circulating triglyceride level ( J:346448 )

• triglyceride levels are reduced at 24 weeks of age

increased circulating aspartate transaminase level ( J:346448 )

• the aspartate aminotransferase (AST) to alanine aminotransferase (ALT) level ratio is increased at 24 weeks of age, indicating liver injury

improved glucose tolerance ( J:346448 )

• mice show increased glucose tolerance at 24 weeks of age

insulin resistance ( J:346448 )

• mice show reduced insulin sensitivity at 24 weeks of age and systemic insulin resistance is seen in 36-week-old mice

• mice develop cardiac insulin resistance as indicated by decreased IRS-1/2 expression in hearts

• injection with AAV9-cTNT-myocardin at 16 weeks of age increases IRS-1 expression but does not restore IRS-2 expression

decreased circulating adiponectin level ( J:346448 )

• plasma adiponectin levels are reduced at 24 weeks of age

increased liver cholesterol level ( J:346448 )

• at 24 weeks of age

increased liver free fatty acids level ( J:346448 )

• at 24 weeks of age

increased liver triglyceride level ( J:346448 )

• at 8 and 24 weeks of age

liver/biliary system

increased liver weight ( J:346448 )

increased liver cholesterol level ( J:346448 )

• at 24 weeks of age

increased liver free fatty acids level ( J:346448 )

• at 24 weeks of age

increased liver triglyceride level ( J:346448 )

• at 8 and 24 weeks of age

hepatic steatosis ( J:346448 )

• hepatic steatosis is evident at 8 weeks of age

muscle

increased myocardial fiber size ( J:346448 )

• increase in size of cardiomyocytes

• mice injected with AAV9-cTNT-myocardin at 16 weeks of age show reduced cardiomyocyte size

decreased cardiac muscle contractility ( J:346448 )

• at 28 weeks of age, percent ejection fraction and percent fractional shortening are reduced by 59.4% and 31.2%, respectively, compared to 84.3% and 52.6% in controls and there is only a minor decrease in percent ejection fraction and percent fractional shorting in mice aged 36 weeks compared to those at 26 week of age, indicating slow progression of congestive heart failure

• mice injected with AAV9-cTNT-myocardin at 16 weeks of age increases percent ejection fraction and percent fractional shortening to levels comparable to controls

• treatment with Rosiglitazone, a systemic insulin sensitizer, improves cardiac metabolism and function

cellular

increased fibroblast proliferation ( J:346448 )

• staining for FSP, a biomarker for fibroblasts, is increased in hearts, suggesting enhanced proliferation of cardiac fibroblasts

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
cardiomyopathy		DOID:0050700		J:346448
lipodystrophy		DOID:811		J:346448