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PMID: 15760270 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

PLoS biology ·Vol. 3 ·No. 4 ·2005-04-00 ·Pages e101

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

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.

MeSH Terms
Animals Body Weight/genetics Cerebrovascular Disorders/genetics Exons Fatty Liver/enzymology,genetics Female Insulin Resistance/genetics Male Mice Mice, Knockout Molecular Sequence Data Muscular Diseases/enzymology,genetics Obesity/genetics Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Trans-Activators/deficiency,genetics Transcription Factors Transcription, Genetic
Chemicals
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Ppargc1a protein, mouse Trans-Activators Transcription Factors
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Leone Teresa C
Center for Cardiovascular Research, Washington University School of Medicine, St Louis, Missouri, USA.
Lehman John J
Finck Brian N
Schaeffer Paul J
Wende Adam R
Boudina Sihem
Courtois Michael
Wozniak David F
Sambandam Nandakumar
Bernal-Mizrachi Carlos
Chen Zhouji
Holloszy John O
Medeiros Denis M
Schmidt Robert E
Saffitz Jeffrey E
Abel E Dale
Semenkovich Clay F
Kelly Daniel P
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Article Info
Journal
PLoS biology
Abbr.
PLoS Biol
ISSN
1545-7885
DOI
10.1371/journal.pbio.0030101
Published
2005-04-00
Epub
2005-00-15
Pages
e101
Language
English
Region
United States
NLM ID
101183755
PMCID
PMC1064854
Subset
IM
Grants
NHLBI NIH HHS · P01 HL57278 · United States
NHLBI NIH HHS · R01 HL058427 · United States
NIA NIH HHS · K08 AG24844 · United States
NIDDK NIH HHS · P30 DK056341 · United States
NIDDK NIH HHS · P30 DK56341 · United States
NHLBI NIH HHS · R01 HL70070 · United States
NIDDK NIH HHS · R01 DK045416 · United States
NHLBI NIH HHS · R01 HL58427 · United States
NIDDK NIH HHS · P30 DK52574 · United States
NHLBI NIH HHS · P01 HL057278 · United States
NIDDK NIH HHS · P30 DK052574 · United States
NHLBI NIH HHS · R01 HL070070 · United States
NIA NIH HHS · K08 AG024844 · United States
NIDDK NIH HHS · R01 DK45416 · United States
Databases
GENBANK
AF335420
External Links
PubMed source DOI: 10.1371/journal.pbio.0030101 PMC Full Text View journal details
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