Phenotypes associated with this allele

• Allele Symbol: Ppargc1a^tm1Dpk
• Allele Name: targeted mutation 1, Daniel P Kelly
• Allele ID: MGI:3522468
• Summary: 7 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk	B6.129X1-Ppargc1a^tm1Dpk/J	MGI:6489606
hm2	Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk	involves: 129X1/SvJ	MGI:3802667
hm3	Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk	involves: 129X1/SvJ * C57BL/6	MGI:3530153
cn4	Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk Ppargc1b^tm1Dpk/Ppargc1b^tm1Dpk Tg(Myh6-cre)2182Mds/0	involves: 129X1/SvJ * FVB/N	MGI:3802663
cx5	Htt^tm1Mfc/Htt^+ Ppargc1a^tm1Dpk/Ppargc1a^+	involves: 129S1/Sv * 129X1/SvJ	MGI:3698750
cx6	Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk Ppargc1b^tm1.1Dpk/Ppargc1b^tm1.1Dpk	involves: 129X1/SvJ * FVB/N	MGI:3802666
cx7	Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk Ppargc1b^tm1.1Dpk/Ppargc1b^+	involves: 129X1/SvJ * FVB/N	MGI:3802665

Genotype
MGI:6489606

hm1

• Allelic Composition: Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk
• Genetic Background: B6.129X1-Ppargc1a^tm1Dpk/J

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

behavior/neurological

impaired coordination ( J:298664 )

• motor coordination is severely impaired in middle-aged (10 months of age) mice and even further in old (20 months of age) mice on the accelerating rotarod

decreased locomotor activity ( J:298664 )

• a group of 10-month old and 20-month old mice show fewer spontaneous, voluntary movements in the open field

bradykinesia ( J:298664 )

• old mice at 20 months of age exhibit significant bradykinesia during pole testing

homeostasis/metabolism

decreased nervous system dopamine level ( J:298664 )

• levels of dopamine and its metabolites (DOPAC and HVA) in the striatum are reduced in 10-month old mice and are even further reduced in 20-month old mice

nervous system

abnormal substantia nigra morphology ( J:298664 )

• mice exhibit reduced expression of mitochondrial markers in the substantia nigra

neurodegeneration ( J:298664 )

• mice exhibit age-related dopaminergic neurodegeneration, with a significant reduction in TH+ neurons at 20 months of age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Parkinson's disease		DOID:14330	OMIM:PS168600	J:298664

Genotype
MGI:3802667

hm2

• Allelic Composition: Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk
• Genetic Background: involves: 129X1/SvJ

adipose tissue

abnormal brown adipose tissue morphology ( J:137598 )

• triglyceride content of brown adipose tissue is increased compared to in wild-type mice

• mitochondria density is decreased compared to in wild-type mice

• brown adipose tissue mitochondria exhibit reduced cristae density compared to in wild-type mice

abnormal fat cell morphology ( J:137598 )

• brown adipocytes exhibit increased lipid droplet size and density compared to in wild-type mice

homeostasis/metabolism

decreased triglyceride level ( J:137598 )

• triglyceride content of brown adipose tissue is increased compared to in wild-type mice

cardiovascular system

abnormal blood circulation ( J:137598 )

• heart performance is reduced compared to in wild-type mice but not as severely as in Ppargc1a^tm1Dpk Ppargc1b^tm1.1Dpk homozygotes

Genotype
MGI:3530153

hm3

• Allelic Composition: Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk
• Genetic Background: involves: 129X1/SvJ * C57BL/6

Hepatic steatosis develops in fasted Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk mice

adipose tissue

increased total body fat amount ( J:96306 )

• 7 month or older males accumulated more body fat than controls

increased percent body fat/body weight ( J:96306 )

• percent body fat in 18- and 24-week old females but not males was greater than in wildtype and saw no differences in lean mass

behavior/neurological

increased thigmotaxis ( J:96306 )

• homozygous mutants made significantly fewer entries into, spent significantly less time in, and traveled a significantly shorter distance in the central area of the field, although differences in distance traveled in the peripheral zone of the field was not significantly different from controls

decreased grip strength ( J:96306 )

• impaired strength as homozygotes were unable to remain on an inverted screen for the same length of time as wildtype but did not differ in the times that it took to turn around and climb to the top of screens

abnormal locomotor behavior ( J:96306 )

• homozygous mutants exhibited a significantly lower mean number of ambulations and rearings over a one hour period

fatigue ( J:96306 )

• homozygous mutants exhibited a reduced capacity to sustain running exercise on a motorized treadmill at 3.5 and 6-8 months of age

cardiovascular system

decreased heart weight ( J:96306 )

• weight of the heart, but not brain. liver, kidney or brown adipose tissue (BAT), was significantly lower in 3 and 8 week old mutants

decreased cardiac output ( J:96306 )

• hearts isolated from homozygous mutants generated lower cardiac work due to a reduced cardiac output than in wildtype

decreased ventricle muscle contractility ( J:96306 )

• left ventricular fractional shortening was decreased in 6-8 month old females during the first 4 minutes after exercise

decreased heart rate ( J:96306 )

• 6-8 month old females exhibited an inappropriate decline in the mean heart rate after exercise

• 10-12 week old mice exhibited a significantly blunted heart rate response to beta-adrenergic stimulation

cellular

abnormal cellular respiration ( J:96306 )

• mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle

• soleus muscle had a defect in state 3 (ADP-stimulated) mitochondrial respiration, but not state 2 (basal) or state 4 respiration

• isolated hepatocytes exhibited a modest but significant reduction in both state 2 (basal) and 3 (ADP-stimulated) mitochondrial respiration rates

growth/size/body

abnormal body weight ( J:96306 )

• 15-20% reduction in total body mass 1 week after birth with this difference disappearing by 3 weeks of age

• modest but significant increase in body weight at 18 weeks of age

increased susceptibility to weight gain ( J:96306 )

• modest but significant increase in body weight at 18 weeks of age with no differences in food intake or general activity

homeostasis/metabolism

impaired adaptive thermogenesis ( J:96306 )

• 28-37 day old mutants but not older mice, exhibited a markedly abnormal drop in core temperature (by 12C versus 3C in wildtype) when exposed to 4C for 5 hours

decreased oxygen consumption ( J:96306 )

• the VO_2max (maximum oxygen consumption, measured in milliliters of oxygen per kilogram of body weight per minute) was significantly lower in homozygous mutants than in wildtype when exercised on a rigorous treadmill protocol

improved glucose tolerance ( J:96306 )

• females on a high-fat diet were significantly more glucose tolerant compared to wildtype

increased insulin sensitivity ( J:96306 )

• females on a high-fat diet were significantly more insulin sensitive compared to wildtype

liver/biliary system

hepatic steatosis ( J:96306 )

• under basal conditions, the liver was normal, however following a 24 hour fast, homozygous mutants exhibited hepatic steatosis but showed no differences in plasma triglycerides or free fatty acids in fed or fasted states

abnormal liver physiology ( J:96306 )

• isolated hepatocytes exhibited a modest but significant reduction in both state 2 (basal) and 3 (ADP-stimulated) mitochondrial respiration rates

• hepatocytes treated with oleate accumulated more neutral lipid and had significantly lower rates of ³H-palmitate oxidation, indicating reduced capacity for fat oxidation

• triglyceride synthesis rate was increased nearly 50% in isolated homozygous mutant hepatocytes

muscle

decreased ventricle muscle contractility ( J:96306 )

• left ventricular fractional shortening was decreased in 6-8 month old females during the first 4 minutes after exercise

decreased gastrocnemius weight ( J:96306 )

• weight of the gastrocnemius was significantly lower in 3 and 8 week old mutants

decreased soleus weight ( J:96306 )

• weight of the soleus was significantly lower in 3 and 8 week old mutants

abnormal skeletal muscle fiber morphology ( J:96306 )

• fewer and smaller mitochondria and a reduction in the expression of nuclear genes involved in mitochondrial electron transport and oxidative phosphorylation were observed in the slow twitch fiber-enriched soleus muscle of 1 month old mutants, however no differences in mitochondrial ultrastructure were seen in the heart or BAT

• soleus muscle had a defect in state 3 (ADP-stimulated) mitochondrial respiration, but not state 2 (basal) or state 4 respiration

decreased skeletal muscle weight ( J:96306 )

• weights of slow twitch fiber-enriched skeletal muscles, including gastrocnemius and soleus, but not the less oxidative tibialis anterior, were significantly lower at 3 and 8 weeks of age

increased muscle fatigability ( J:96306 )

• capacity to generate force following a series of tetani in soleus muscle was significantly lower in homozygous mutants, however there was no difference in force generation during the initial phase of stimulation, indicating muscle fatigability

nervous system

abnormal brainstem morphology ( J:96306 )

• observed areas of microvacuolation in multiple brainstem regions

abnormal basal ganglion morphology ( J:96306 )

• observed microvacuolation of the neuropil and neurons of the basal ganglia (caudate and putamen)

abnormal hippocampus morphology ( J:96306 )

• the hippocampus showed neuronal microvacuolation

abnormal cerebral cortex morphology ( J:96306 )

• observed patchy areas of microvacuolation involving the neuropil and individual pyramidal neurons of the deep layers of the cerebral cortex

abnormal cerebellum morphology ( J:96306 )

• rare vacuolated Purkinje and granule cell neurons were identified in the cerebellar cortex

limbs/digits/tail

decreased gastrocnemius weight ( J:96306 )

• weight of the gastrocnemius was significantly lower in 3 and 8 week old mutants

decreased soleus weight ( J:96306 )

• weight of the soleus was significantly lower in 3 and 8 week old mutants

Genotype
MGI:3802663

cn4

• Allelic Composition: Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk; Ppargc1b^tm1Dpk/Ppargc1b^tm1Dpk; Tg(Myh6-cre)2182Mds/0
• Genetic Background: involves: 129X1/SvJ * FVB/N

mortality/aging

neonatal lethality, incomplete penetrance ( J:137598 )

• 67% of mice die within 24 hours of birth

postnatal lethality, complete penetrance ( J:137598 )

• all mice die by day 7

cardiovascular system

abnormal myocardium layer morphology ( J:137598 )

• after birth, myocytes exhibit a reduction in mitochondrial number and size compared to in wild-type mice

decreased cardiac output ( J:137598 )

• similar to that found in Ppargc1a^tm1Dpk Ppargc1b^tm1.1Dpk homozygotes

muscle

abnormal myocardium layer morphology ( J:137598 )

• after birth, myocytes exhibit a reduction in mitochondrial number and size compared to in wild-type mice

Genotype
MGI:3698750

cx5

• Allelic Composition: Htt^tm1Mfc/Htt⁺; Ppargc1a^tm1Dpk/Ppargc1a⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

behavior/neurological

impaired coordination ( J:116058 )

• rotarod performance is severely impaired and much worse than in mice carrying the Hdh^tm1Mfc knock-in allele

nervous system

abnormal striatum morphology ( J:116058 )

• striatal neuronal volumes are significantly decreased in 6-month old mutants compared to mice carrying the Hdh^tm1Mfc knock-in allele

neuron degeneration ( J:116058 )

• early neuronal degeneration appears in the striatum and the medial septal nucleus by 3 months of age

• mutants exhibit increased susceptibility to 3-nitropropionic acid, developing larger striatal lesions and increased number of degenerating neurons compared to mice carrying the Hdh^tm1Mfc knock-in allele

Genotype
MGI:3802666

cx6

• Allelic Composition: Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk; Ppargc1b^tm1.1Dpk/Ppargc1b^tm1.1Dpk
• Genetic Background: involves: 129X1/SvJ * FVB/N

mortality/aging

neonatal lethality, incomplete penetrance ( J:137598 )

• 70% of mice die within 24 hours of birth

postnatal lethality, complete penetrance ( J:137598 )

• all mice die prior to day 14

cardiovascular system

abnormal myocardium layer morphology ( J:137598 )

• mitochondria in heart samples are small and sparse in postnatal ventricular sections compared to in wild-type mice

• after birth, some myocytes are largely or partially devoid of mitochondria, sacomeres and other cellular organelles

• heart cells exhibit a decrease in mitochondrial number and size, abnormal vacuoles and reduced cristae density compared to in wild-type mice

• despite normal myofibrillar volume, cellular mitochondrial and sarcomere volume densities are reduced compared to in wild-type mice

• mitochondria fail to exhibit an increase in mitochondrial density at E17.5 and P0.5 unlike in wild-type mice

• perinatal mitochondrial biogenesis is blocked

abnormal heart development ( J:137598 )

• mice exhibit a general arrest in cardiac maturation

• at P0.5, mice fail to exhibit an increase in cardiac biogenesis observed in wild-type mice

small heart ( J:137598 )

abnormal heart left ventricle morphology ( J:137598 )

• 12 hours after birth, left ventricle diameter is reduced during diastole compared to in wild-type mice

decreased heart left ventricle weight ( J:137598 )

• at 12 hours after birth

abnormal blood circulation ( J:137598 )

• passive and artrial contraction components of diastolic left ventricle filling are uncoupled from systolic left ventricle outflow jet unlike in wild-type mice consistent with intermittent second-degree heart block

• mice exhibit an increase in isovolumic contraction time and isovolumic relaxation time and decreased ejection time compared to wild-type mice

• mice exhibit decreased passive (E) to active (A) ratio and prolonged isovolumic relaxation time consistent with impaired ventricular diastolic relaxation unlike in wild-type mice

decreased cardiac output ( J:137598 )

• despite preservation of left ventricle fractional shortening, cardiac output is reduced compared to in wild-type mice

decreased heart rate ( J:137598 )

• at 12 hours after birth

congestive heart failure ( J:137598 )

adipose tissue

abnormal brown adipose tissue morphology ( J:137598 )

• triglyceride content of brown adipose tissue is increased compared to in wild-type mice

• brown adipose tissue mitochondrial and cristae density are less than in wild-type mice

• brown adipocytes exhibit increased lipid droplet size and density compared to in wild-type mice and single homozygotes

abnormal fat cell morphology ( J:137598 )

• brown adipocytes exhibit increased lipid droplet size and density compared to in wild-type mice and single homozygotes

respiratory system

abnormal pulmonary alveolus morphology ( J:137598 )

• postmortem of mice that die within 24 hours of birth reveal alveolar collapse

• however, alveolar morphology is normal prior to death

respiratory distress ( J:137598 )

• at birth, mice exhibit labored breathing

homeostasis/metabolism

decreased circulating glucose level ( J:137598 )

• modesty lower at birth

decreased triglyceride level ( J:137598 )

• triglyceride content of brown adipose tissue is increased compared to in wild-type mice

growth/size/body

decreased body weight ( J:137598 )

• at birth

muscle

abnormal myocardium layer morphology ( J:137598 )

• mitochondria in heart samples are small and sparse in postnatal ventricular sections compared to in wild-type mice

• after birth, some myocytes are largely or partially devoid of mitochondria, sacomeres and other cellular organelles

• heart cells exhibit a decrease in mitochondrial number and size, abnormal vacuoles and reduced cristae density compared to in wild-type mice

• despite normal myofibrillar volume, cellular mitochondrial and sarcomere volume densities are reduced compared to in wild-type mice

• mitochondria fail to exhibit an increase in mitochondrial density at E17.5 and P0.5 unlike in wild-type mice

• perinatal mitochondrial biogenesis is blocked

Genotype
MGI:3802665

cx7

• Allelic Composition: Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk; Ppargc1b^tm1.1Dpk/Ppargc1b⁺
• Genetic Background: involves: 129X1/SvJ * FVB/N

homeostasis/metabolism

impaired adaptive thermogenesis ( J:137598 )

• mice exhibit reduced capacity to regulate core temperature after 2 hours of cold exposure compared to wild-type and Ppargc1b^tm1.1Dpk homozygotes