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

Academic Article

Abstract

  • 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.
  • Authors

    Published In

  • PLoS Biology  Journal
  • Keywords

  • Animals, Body Weight, Cerebrovascular Disorders, Exons, Fatty Liver, Female, Insulin Resistance, Male, Mice, Mice, Knockout, Molecular Sequence Data, Muscular Diseases, Obesity, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Trans-Activators, Transcription Factors, Transcription, Genetic
  • Digital Object Identifier (doi)

    Authorlist

  • Leone TC; Lehman JJ; Finck BN; Schaeffer PJ; Wende AR; Boudina S; Courtois M; Wozniak DF; Sambandam N; Bernal-Mizrachi C
  • Start Page

  • e101
  • Volume

  • 3
  • Issue

  • 4