Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle.
Skeletal and cardiac muscle depend on high turnover of ATP made by mitochondria in order to contract efficiently. The transcriptional coactivator PGC-1alpha has been shown to function as a major regulator of mitochondrial biogenesis and respiration in both skeletal and cardiac muscle, but this has been based only on gain-of-function studies. Using genetic knockout mice, we show here that, while PGC-1alpha KO mice appear to retain normal mitochondrial volume in both muscle beds, expression of genes of oxidative phosphorylation is markedly blunted. Hearts from these mice have reduced mitochondrial enzymatic activities and decreased levels of ATP. Importantly, isolated hearts lacking PGC-1alpha have a diminished ability to increase work output in response to chemical or electrical stimulation. As mice lacking PGC-1alpha age, cardiac dysfunction becomes evident in vivo. These data indicate that PGC-1alpha is vital for the heart to meet increased demands for ATP and work in response to physiological stimuli.
Arany
Zoltan
Z
Dana Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
He
Huamei
H
Lin
Jiandie
J
Hoyer
Kirsten
K
Handschin
Christoph
C
Toka
Okan
O
Ahmad
Ferhaan
F
Matsui
Takashi
T
Chin
Sherry
S
Wu
Pei-Hsuan
PH
Rybkin
Igor I
II
Shelton
John M
JM
Manieri
Monia
M
Cinti
Saverio
S
Schoen
Frederick J
FJ
Bassel-Duby
Rhonda
R
Rosenzweig
Anthony
A
Ingwall
Joanne S
JS
Spiegelman
Bruce M
BM
D000818:Animals; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors