PGC-1α deficiency causes multi-system energy metabolic derangements: Muscle dysfunction, abnormal weight control and hepatic steatosis

Teresa C. Leone, John J. Lehman, Brian N. Finck, Paul J. Schaeffer, Adam R. Wende, Sihem Boudina, Michael Courtois, David F. Wozniak, Nandakumar Sambandam, Carlos Bernal-Mizrachi, Zhouji Chen, John O. Holloszy, Denis M. Medeiros, Robert E. Schmidt, Jeffrey E. Saffitz, E. Dale Abel, Clay F. Semenkovich, Daniel P. Kelly

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Abstract

The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was targeted in mice. PGC-1α null (PGC-1α-/-) 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-1α-/- mice. With age, the PGC-1α-/- 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-1α -/- mice, leading to reduced muscle performance and exercise capacity. PGC-1α-/- mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1α-/- mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1α-/- mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1α-/- 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-1α-/- mice. These results demonstrate that PGC-1α is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

Original languageEnglish
Pages (from-to)672-687
Number of pages16
JournalPLoS biology
Volume3
Issue number4
DOIs
StatePublished - Apr 1 2005

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    Leone, T. C., Lehman, J. J., Finck, B. N., Schaeffer, P. J., Wende, A. R., Boudina, S., Courtois, M., Wozniak, D. F., Sambandam, N., Bernal-Mizrachi, C., Chen, Z., Holloszy, J. O., Medeiros, D. M., Schmidt, R. E., Saffitz, J. E., Abel, E. D., Semenkovich, C. F., & Kelly, D. P. (2005). PGC-1α deficiency causes multi-system energy metabolic derangements: Muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS biology, 3(4), 672-687. https://doi.org/10.1371/journal.pbio.0030101