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.
Leone
Teresa C
TC
Center for Cardiovascular Research, Washington University School of Medicine, St Louis, Missouri, USA.
Lehman
John J
JJ
Finck
Brian N
BN
Schaeffer
Paul J
PJ
Wende
Adam R
AR
Boudina
Sihem
S
Courtois
Michael
M
Wozniak
David F
DF
Sambandam
Nandakumar
N
Bernal-Mizrachi
Carlos
C
Chen
Zhouji
Z
Holloszy
John O
JO
Medeiros
Denis M
DM
Schmidt
Robert E
RE
Saffitz
Jeffrey E
JE
Abel
E Dale
ED
Semenkovich
Clay F
CF
Kelly
Daniel P
DP
D000818:Animals; D001835:Body Weight / Q000235:genetics; D002561:Cerebrovascular Disorders / Q000235:genetics; D005091:Exons; D005234:Fatty Liver / Q000201:enzymology / Q000235:genetics*; D005260:Female; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000201:enzymology / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics*; D014157:Transcription Factors; D014158:Transcription, Genetic
D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors