Ppargc1a<tm1Dpk> Targeted Allele Detail MGI Mouse (MGI:3522468)

Ppargc1a^tm1Dpk
Targeted Allele Detail

Nomenclature

Symbol:	Ppargc1a^tm1Dpk
Name:	peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; targeted mutation 1, Daniel P Kelly
MGI ID:	MGI:3522468
Synonyms:	PGC-1alpha^-
Gene:	Ppargc1a Location: Chr5:51845488-51958964 bp, - strand Genetic Position: Chr5, cytoband C1

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

Show the 2 image(s) involving this allele.

Mutation
origin

Germline Transmission:	Earliest citation of germline transmission: J:96306
Parent Cell Line:	RW-4 (ES Cell)
Strain of Origin:	129X1/SvJ

Mutation
description

Allele Type:	Targeted (knock-out)
Mutations:	Insertion, Other
	The targeting event for this knock-out resulted in a 3 prime end recombination and an insertion on the 5 prime end causing an additional exon 3 in the allele downstream of exon 5. This additional exon 3 causes a premature stop codon at amino acid 255 and an unstable transcript (no smaller proteins were identified by Western blot analysis). RT-PCR, Northern and Western blot analysis confirmed the absence of a stable transcript and no detectable protein. (J:96306)

Find Mice (IMSR)

Mouse strains and cell lines available from the International Mouse Strain Resource (IMSR)

Carrying this Mutation:	Mouse Strains: 1 strain available Cell Lines: 0 lines available
Carrying any Ppargc1a Mutation:	4 strains or lines available

Phenotype
summary

Phenotype Summary by Mammalian Phenotype terms

(show or hide all annotated terms)

Genotypes are listed in the next section.

Key:

hm	homozygous	ht	heterozygous
cn	conditional genotype	cx	complex: > 1 genome feature
tg	involves transgenes	ot	other: hemizygous, indeterminate,...
N	normal phenotype		expected model not found

Affected Systems	Genotypes:	hm1	hm2	cn3	cx4	cx5	cx6
adipose tissue		√	√				√
abnormal brown adipose tissue morphology		√					√
abnormal fat cell morphology		√					√
increased percent body fat			√
increased adipose tissue amount			√
		hm1	hm2	cn3	cx4	cx5	cx6
behavior/neurological			√		√
increased thigmotaxis			√
abnormal grip strength			√
abnormal locomotor activity			√
fatigue			√
impaired coordination					√
		hm1	hm2	cn3	cx4	cx5	cx6
cardiovascular system		√	√	√			√
abnormal blood circulation		√					√
decreased cardiac output			√	√			√
decreased ventricle muscle contractility			√
decreased heart rate			√				√
abnormal cardiac muscle morphology				√			√
abnormal heart development							√
small heart							√
decreased heart weight			√
decreased heart left ventricle weight							√
abnormal heart left ventricle morphology							√
congestive heart failure							√
		hm1	hm2	cn3	cx4	cx5	cx6
cellular			√
decreased mitochondrial oxidation			√
		hm1	hm2	cn3	cx4	cx5	cx6
growth/size			√				√
abnormal body weight			√
weight gain			√
decreased body weight							√
		hm1	hm2	cn3	cx4	cx5	cx6
homeostasis/metabolism		√	√			√	√
decreased triglyceride level		√					√
abnormal body temperature regulation			√			√
decreased oxygen consumption			√
improved glucose tolerance			√
increased insulin sensitivity			√
decreased circulating glucose level							√
		hm1	hm2	cn3	cx4	cx5	cx6
lethality/postnatal				√			√
postnatal lethality				√			√
		hm1	hm2	cn3	cx4	cx5	cx6
lethality/prenatal-perinatal				√			√
neonatal lethality				√			√
		hm1	hm2	cn3	cx4	cx5	cx6
liver/biliary system			√
hepatic steatosis			√
abnormal liver physiology			√
		hm1	hm2	cn3	cx4	cx5	cx6
muscle			√	√			√
decreased ventricle muscle contractility			√
abnormal skeletal muscle morphology			√
abnormal skeletal muscle fiber morphology			√
decreased gastrocnemius weight			√
decreased soleus weight			√
muscle fatigue			√
abnormal cardiac muscle morphology				√			√
		hm1	hm2	cn3	cx4	cx5	cx6
nervous system			√		√
abnormal brainstem morphology			√
abnormal basal ganglion morphology			√
abnormal striatum morphology					√
abnormal hippocampus morphology			√
abnormal cerebral cortex morphology			√
abnormal cerebellum morphology			√
neuron degeneration					√
		hm1	hm2	cn3	cx4	cx5	cx6
respiratory system							√
abnormal respiratory alveoli morphology							√
respiratory distress							√

Phenotypic
data by
genotype

Phenotypic Data by Genotype

(show or hide all phenotypic details)

Genotype	Allelic Composition	Genetic Background
hm1	Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk	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	Allelic Composition	Genetic Background
hm2	Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk	involves: 129X1/SvJ * C57BL/6
Hepatic steatosis develops in fasted Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk mice adipose tissue increased percent body fat (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 increased adipose tissue amount (J:96306) 7 month or older males accumulated more body fat than controls 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 abnormal 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 activity (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 decreased mitochondrial oxidation (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 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 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 abnormal body temperature regulation (J:96306) 28-37 day old mutants but not older mice, exhibited a markedly abnormal drop in core temperature (by 12�C versus 3�C in wildtype) when exposed to 4�C 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 abnormal skeletal muscle morphology (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 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 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 muscle fatigue (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
Genotype	Allelic Composition	Genetic Background
cn3	Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk Ppargc1b^tm1Dpk/Ppargc1b^tm1Dpk Tg(Myh6-cre)2182Mds/0	involves: 129X1/SvJ * FVB/N
lethality/prenatal-perinatal neonatal lethality (J:137598) 67% of mice die within 24 hours of birth lethality/postnatal postnatal lethality (J:137598) all mice die by day 7 cardiovascular system abnormal cardiac muscle 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 Ppargc1atm1Dpk Ppargc1b^tm1.1Dpk homozygotes muscle abnormal cardiac muscle morphology (J:137598) after birth, myocytes exhibit a reduction in mitochondrial number and size compared to in wild-type mice
Genotype	Allelic Composition	Genetic Background
cx4	Htt^tm1Mfc/Htt⁺ Ppargc1a^tm1Dpk/Ppargc1a⁺	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	Allelic Composition	Genetic Background
cx5	Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk Ppargc1b^tm1.1Dpk/Ppargc1b⁺	involves: 129X1/SvJ * FVB/N
homeostasis/metabolism abnormal body temperature regulation (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
Genotype	Allelic Composition	Genetic Background
cx6	Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk Ppargc1b^tm1.1Dpk/Ppargc1b^tm1.1Dpk	involves: 129X1/SvJ * FVB/N
lethality/prenatal-perinatal neonatal lethality (J:137598) 70% of mice die within 24 hours of birth lethality/postnatal postnatal lethality (J:137598) all mice die prior to day 14 cardiovascular system 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 abnormal cardiac muscle 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 small heart (J:137598) decreased heart left ventricle weight (J:137598) at 12 hours after birth abnormal heart left ventricle morphology (J:137598) 12 hours after birth, left ventricle diameter is reduced during diastole compared to in wild-type mice 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 respiratory alveoli 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 decreased body weight (J:137598) at birth muscle abnormal cardiac muscle 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

References

Original:	J:96306 Leone TC et al., "PGC-1alpha Deficiency Causes Multi-System Energy Metabolic Derangements: Muscle Dysfunction, Abnormal Weight Control and Hepatic Steatosis." PLoS Biol 2005 Mar 15;3(4):e101
All:	8 reference(s)

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