Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Congenic; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse Generation N9pN1 Generation Definitions   Donating Investigator Daniel Kelly,   Burnham Institute for Medical Research

Description
Mice that are homozygous for the targeted mutation are viable and fertile. During the generation of this allele, a 3' homologous recombination and insertion occurred with a duplication of exon 3 between exons 5 and 6. The exon 3 insertion, which was confirmed by RT-PCR, results in a mutant transcript that encodes a truncated protein due to a stop codon at amino acid 255. Normal gene product (mRNA) containing an exon 5?6 border is not detected. If the truncated protein gene product is stable, it could theoretically have some activity, given that it would contain nuclear receptor-interacting domains and the amino-terminal activation domain. Total body weights for homozygotes are reduced 15-20% for the first week after birth, but become normal by 3 weeks of age. By 18 weeks of age, homozygotes have heavier body weights and increased percent body fat than wildtype controls. Heart and slow twitch skeletal muscle (gastrocnemius, soleus) weights are lower in homozygotes than controls. Electron microscopy analysis reveals lower density and smaller mitochondria in soleus muscle. The state 3 (ADP-stimulated) mitochondrial respiration rate is diminished. Overall activity is decreased and thigmotaxis behavior is increased. Mutant mice exhibit reduced strength, activity endurance capacity, muscle fatigue and reduced cardiac output. Homozygotes are more sensitive to cold temperatures. 24 hour fasting results in hepatic steatosis. 4.5 month old homozygous females exhibit increased body weight, but normal glucose tolerance and insulin sensitivity on standard chow diet. Female homozygotes on high fat chow exhibit mildly increased glucose tolerance and insulin sensitivity. Histological examination of the parietal cerebral cortex, hippocampus, brainstem and basal ganglia reveals microvacuolation. This mutant mouse strain may be useful in studies of mitochondrial respiration and physiology, muscle physiology, and energy metabolism.

Development
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt exons 4 and 5. The construct was electroporated into 129X1/SvJ derived RW-4 embryonic stem (ES) cells. A 3' homologous recombination and insertion occurred with a duplication of exon 3 between exons 5 and 6. The exon 3 insertion, which was confirmed by RT-PCR, results in a mutant transcript that encodes a truncated protein due to a stop codon at amino acid 255. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric animals were crossed to C57BL/6J mice, and then backcrossed to C57BL/6J for 9 generations using a marker assisted (speed congenic) protocol. Upon arrival at The Jackson Laboratory, the mice were crossed to C57BL/6J once to establish the colony.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Ppargc1a

008597	B6.129-Ppargc1atm1Brsp/J
009666	B6.129-Ppargc1atm2Brsp/J
008231	C57BL/6-Tg(Ckm-Ppargc1a)31Brsp/J
012387	FVB-Tg(tetO-Ppargc1a)1Dpk/J

View Strains carrying other alleles of Ppargc1a     (4 strains)

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk

        involves: 129X1/SvJ * C57BL/6

• adipose tissue phenotype
• increased percent body fat
  • 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   (MGI Ref ID J:96306)
• increased total body fat amount
  • 7 month or older males accumulated more body fat than controls   (MGI Ref ID J:96306)
• behavior/neurological phenotype
• abnormal locomotor behavior
  • homozygous mutants exhibited a significantly lower mean number of ambulations and rearings over a one hour period   (MGI Ref ID J:96306)
• decreased grip strength
  • 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   (MGI Ref ID J:96306)
• fatigue
  • homozygous mutants exhibited a reduced capacity to sustain running exercise on a motorized treadmill at 3.5 and 6-8 months of age   (MGI Ref ID J:96306)
• increased thigmotaxis
  • 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   (MGI Ref ID J:96306)
• cardiovascular system phenotype
• decreased cardiac output
  • hearts isolated from homozygous mutants generated lower cardiac work due to a reduced cardiac output than in wildtype   (MGI Ref ID J:96306)
• decreased heart rate
  • 6-8 month old females exhibited an inappropriate decline in the mean heart rate after exercise   (MGI Ref ID J:96306)
  • 10-12 week old mice exhibited a significantly blunted heart rate response to beta-adrenergic stimulation   (MGI Ref ID J:96306)
• decreased heart weight
  • weight of the heart, but not brain. liver, kidney or brown adipose tissue (BAT), was significantly lower in 3 and 8 week old mutants   (MGI Ref ID J:96306)
• decreased ventricle muscle contractility
  • left ventricular fractional shortening was decreased in 6-8 month old females during the first 4 minutes after exercise   (MGI Ref ID J:96306)
• cellular phenotype
• abnormal cellular respiration
  • mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle   (MGI Ref ID J:96306)
  • soleus muscle had a defect in state 3 (ADP-stimulated) mitochondrial respiration, but not state 2 (basal) or state 4 respiration   (MGI Ref ID J:96306)
  • isolated hepatocytes exhibited a modest but significant reduction in both state 2 (basal) and 3 (ADP-stimulated) mitochondrial respiration rates   (MGI Ref ID J:96306)
• growth/size phenotype
• abnormal body weight
  • 15-20% reduction in total body mass 1 week after birth with this difference disappearing by 3 weeks of age   (MGI Ref ID J:96306)
  • modest but significant increase in body weight at 18 weeks of age   (MGI Ref ID J:96306)
• • increased susceptibility to weight gain
    • modest but significant increase in body weight at 18 weeks of age with no differences in food intake or general activity   (MGI Ref ID J:96306)
• homeostasis/metabolism phenotype
• decreased oxygen consumption
  • 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   (MGI Ref ID J:96306)
• impaired adaptive thermogenesis
  • 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   (MGI Ref ID J:96306)
• improved glucose tolerance
  • females on a high-fat diet were significantly more glucose tolerant compared to wildtype   (MGI Ref ID J:96306)
• increased insulin sensitivity
  • females on a high-fat diet were significantly more insulin sensitive compared to wildtype   (MGI Ref ID J:96306)
• liver/biliary system phenotype
• abnormal liver physiology
  • isolated hepatocytes exhibited a modest but significant reduction in both state 2 (basal) and 3 (ADP-stimulated) mitochondrial respiration rates   (MGI Ref ID J:96306)
  • hepatocytes treated with oleate accumulated more neutral lipid and had significantly lower rates of ³H-palmitate oxidation, indicating reduced capacity for fat oxidation   (MGI Ref ID J:96306)
  • triglyceride synthesis rate was increased nearly 50% in isolated homozygous mutant hepatocytes   (MGI Ref ID J:96306)
• hepatic steatosis
  • 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   (MGI Ref ID J:96306)
• muscle phenotype
• abnormal skeletal muscle fiber morphology
  • 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   (MGI Ref ID J:96306)
  • soleus muscle had a defect in state 3 (ADP-stimulated) mitochondrial respiration, but not state 2 (basal) or state 4 respiration   (MGI Ref ID J:96306)
• decreased gastrocnemius weight
  • weight of the gastrocnemius was significantly lower in 3 and 8 week old mutants   (MGI Ref ID J:96306)
• decreased skeletal muscle weight
  • 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   (MGI Ref ID J:96306)
• decreased soleus weight
  • weight of the soleus was significantly lower in 3 and 8 week old mutants   (MGI Ref ID J:96306)
• decreased ventricle muscle contractility
  • left ventricular fractional shortening was decreased in 6-8 month old females during the first 4 minutes after exercise   (MGI Ref ID J:96306)
• muscle fatigue
  • 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   (MGI Ref ID J:96306)
• nervous system phenotype
• abnormal basal ganglion morphology
  • observed microvacuolation of the neuropil and neurons of the basal ganglia (caudate and putamen)   (MGI Ref ID J:96306)
• abnormal brainstem morphology
  • observed areas of microvacuolation in multiple brainstem regions   (MGI Ref ID J:96306)
• abnormal cerebellum morphology
  • rare vacuolated Purkinje and granule cell neurons were identified in the cerebellar cortex   (MGI Ref ID J:96306)
• abnormal cerebral cortex morphology
  • observed patchy areas of microvacuolation involving the neuropil and individual pyramidal neurons of the deep layers of the cerebral cortex   (MGI Ref ID J:96306)
• abnormal hippocampus morphology
  • the hippocampus showed neuronal microvacuolation   (MGI Ref ID J:96306)

Ppargc1a^tm1Dpk/Ppargc1a^tm1Dpk

        involves: 129X1/SvJ

• adipose tissue phenotype
• abnormal brown adipose tissue morphology
  • triglyceride content of brown adipose tissue is increased compared to in wild-type mice   (MGI Ref ID J:137598)
  • mitochondria density is decreased compared to in wild-type mice   (MGI Ref ID J:137598)
  • brown adipose tissue mitochondria exhibit reduced cristae density compared to in wild-type mice   (MGI Ref ID J:137598)
• abnormal fat cell morphology
  • brown adipocytes exhibit increased lipid droplet size and density compared to in wild-type mice   (MGI Ref ID J:137598)
• homeostasis/metabolism phenotype
• decreased triglyceride level
  • triglyceride content of brown adipose tissue is increased compared to in wild-type mice   (MGI Ref ID J:137598)
• cardiovascular system phenotype
• abnormal blood circulation
  • heart performance is reduced compared to in wild-type mice but not as severely as in Ppargc1a^tm1Dpk Ppargc1b^tm1.1Dpk homozygotes   (MGI Ref ID J:137598)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Cardiovascular Research
Other
      altered fat metabolism

Cell Biology Research

Metabolism Research
Exertion Related
Lipid Metabolism

Research Tools
Metabolism Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Ppargc1atm1Dpk
Allele Name		targeted mutation 1, Daniel P Kelly
Allele Type		Targeted (knock-out)
Common Name(s)		PGC-1alpha-;
Mutation Made By		Teresa Leone,   Burnham Institute for Medical Research
Strain of Origin		129X1/SvJ
ES Cell Line Name		RW-4
ES Cell Line Strain		129X1/SvJ
Gene Symbol and Name		Ppargc1a, peroxisome proliferative activated receptor, gamma, coactivator 1 alpha
Chromosome		5
Gene Common Name(s)		A830037N07Rik; ENSMUSG00000079510; Gm11133; LEM6; PGC-1(alpha); PGC-1v; PGC1; PGC1A; PPAR Gamma Coactivator-1; PPAR gamma coactivator 1; PPARGC1; Pgc-1alpha; Pgc-1alphaa; Pgco1; RIKEN cDNA A830037N07 gene; predicted gene 11133; predicted gene, ENSMUSG00000079510;
Molecular Note		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 andan 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. [MGI Ref ID J:96306]

Genotyping

Genotyping Information

Genotyping Protocols

Ppargc1a^tm1Dpk, QPCR
Generic Neo Melt Curve Analysis,

Robotic MCA

Generic Neo Melt Curve Analysis, Melt Curve Analysis

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Leone TC; Lehman JJ; Finck BN; Schaeffer PJ; Wende AR; Boudina S; Courtois M; Wozniak DF; Sambandam N; Bernal-Mizrachi C; Chen Z; O Holloszy J; Medeiros DM; Schmidt RE; Saffitz JE; Abel ED; Semenkovich CF; Kelly DP. 2005. PGC-1alpha Deficiency Causes Multi-System Energy Metabolic Derangements: Muscle Dysfunction, Abnormal Weight Control and Hepatic Steatosis. PLoS Biol 3(4):e101. [PubMed: 15760270]  [MGI Ref ID J:96306]

Additional References

Ppargc1a^tm1Dpk related

Burgess SC; Leone TC; Wende AR; Croce MA; Chen Z; Sherry AD; Malloy CR; Finck BN. 2006. Diminished hepatic gluconeogenesis via defects in tricarboxylic acid cycle flux in peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha)-deficient mice. J Biol Chem 281(28):19000-8. [PubMed: 16670093]  [MGI Ref ID J:114882]

Chang JS; Fernand V; Zhang Y; Shin J; Jun HJ; Joshi Y; Gettys TW. 2012. NT-PGC-1alpha protein is sufficient to link beta3-adrenergic receptor activation to transcriptional and physiological components of adaptive thermogenesis. J Biol Chem 287(12):9100-11. [PubMed: 22282499]  [MGI Ref ID J:183282]

Cui L; Jeong H; Borovecki F; Parkhurst CN; Tanese N; Krainc D. 2006. Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127(1):59-69. [PubMed: 17018277]  [MGI Ref ID J:116058]

Finck BN; Gropler MC; Chen Z; Leone TC; Croce MA; Harris TE; Lawrence JC Jr; Kelly DP. 2006. Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell Metab 4(3):199-210. [PubMed: 16950137]  [MGI Ref ID J:129744]

Hu X; Xu X; Huang Y; Fassett J; Flagg TP; Zhang Y; Nichols CG; Bache RJ; Chen Y. 2008. Disruption of sarcolemmal ATP-sensitive potassium channel activity impairs the cardiac response to systolic overload. Circ Res 103(9):1009-17. [PubMed: 18802029]  [MGI Ref ID J:155290]

Kiebish MA; Young DM; Lehman JJ; Han X. 2012. Chronic caloric restriction attenuates a loss of sulfatide content in PGC-1alpha-/- mouse cortex: a potential lipidomic role of PGC-1alpha in neurodegeneration. J Lipid Res 53(2):273-81. [PubMed: 22114039]  [MGI Ref ID J:180592]

Lai L; Leone TC; Zechner C; Schaeffer PJ; Kelly SM; Flanagan DP; Medeiros DM; Kovacs A; Kelly DP. 2008. Transcriptional coactivators PGC-1{alpha} and PGC-l{beta} control overlapping programs required for perinatal maturation of the heart. Genes Dev 22(14):1948-61. [PubMed: 18628400]  [MGI Ref ID J:137598]

Lehman JJ; Boudina S; Banke NH; Sambandam N; Han X; Young DM; Leone TC; Gross RW; Lewandowski ED; Abel ED; Kelly DP. 2008. The transcriptional coactivator PGC-1alpha is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis. Am J Physiol Heart Circ Physiol 295(1):H185-96. [PubMed: 18487436]  [MGI Ref ID J:138209]

Li D; Zhang Y; Xu L; Zhou L; Wang Y; Xue B; Wen Z; Li P; Sang J. 2010. Regulation of gene expression by FSP27 in white and brown adipose tissue. BMC Genomics 11:446. [PubMed: 20649970]  [MGI Ref ID J:162769]

Mitra R; Nogee DP; Zechner JF; Yea K; Gierasch CM; Kovacs A; Medeiros DM; Kelly DP; Duncan JG. 2012. The transcriptional coactivators, PGC-1alpha and beta, cooperate to maintain cardiac mitochondrial function during the early stages of insulin resistance. J Mol Cell Cardiol 52(3):701-10. [PubMed: 22080103]  [MGI Ref ID J:183668]

Potthoff MJ; Inagaki T; Satapati S; Ding X; He T; Goetz R; Mohammadi M; Finck BN; Mangelsdorf DJ; Kliewer SA; Burgess SC. 2009. FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci U S A 106(26):10853-8. [PubMed: 19541642]  [MGI Ref ID J:150831]

Schulz E; Dopheide J; Schuhmacher S; Thomas SR; Chen K; Daiber A; Wenzel P; Munzel T; Keaney JF Jr. 2008. Suppression of the JNK pathway by induction of a metabolic stress response prevents vascular injury and dysfunction. Circulation 118(13):1347-57. [PubMed: 18809807]  [MGI Ref ID J:158043]

Xiang Z; Valenza M; Cui L; Leoni V; Jeong HK; Brilli E; Zhang J; Peng Q; Duan W; Reeves SA; Cattaneo E; Krainc D. 2011. Peroxisome-Proliferator-Activated Receptor Gamma Coactivator 1 {alpha} Contributes to Dysmyelination in Experimental Models of Huntington's Disease. J Neurosci 31(26):9544-9553. [PubMed: 21715619]  [MGI Ref ID J:174060]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice can be bred as homozygotes.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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