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PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis.

The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) was targeted in mice. PGC-1alpha null (PGC-1alpha(-/-)) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1alpha(-/-) mice. With age, the PGC-1alpha(-/-) mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1alpha(-/-) mice, leading to reduced muscle performance and exercise capacity. PGC-1alpha(-/-) mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1alpha(-/-) mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1alpha(-/-) mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1alpha(-/-) mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1alpha(-/-) mice. These results demonstrate that PGC-1alpha is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

Pubmed ID: 15760270

Authors

  • Leone TC
  • Lehman JJ
  • Finck BN
  • Schaeffer PJ
  • Wende AR
  • Boudina S
  • Courtois M
  • Wozniak DF
  • Sambandam N
  • Bernal-Mizrachi C
  • Chen Z
  • Holloszy JO
  • Medeiros DM
  • Schmidt RE
  • Saffitz JE
  • Abel ED
  • Semenkovich CF
  • Kelly DP

Journal

PLoS biology

Publication Data

April 11, 2005

Associated Grants

  • Agency: NIA NIH HHS, Id: K08 AG24844
  • Agency: NHLBI NIH HHS, Id: P01 HL57278
  • Agency: NIDDK NIH HHS, Id: P30 DK52574
  • Agency: NIDDK NIH HHS, Id: P30 DK56341
  • Agency: NIDDK NIH HHS, Id: R01 DK45416
  • Agency: NHLBI NIH HHS, Id: R01 HL58427
  • Agency: NHLBI NIH HHS, Id: R01 HL70070

Mesh Terms

  • Animals
  • Body Weight
  • Cerebrovascular Disorders
  • Exons
  • Fatty Liver
  • Female
  • Insulin Resistance
  • Male
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Muscular Diseases
  • Obesity
  • Trans-Activators
  • Transcription Factors
  • Transcription, Genetic