TY - JOUR
T1 - The transcriptional coactivator PGC-1α is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis
AU - Lehman, John J.
AU - Boudina, Sihem
AU - Banke, Natasha Hausler
AU - Sambandam, Nandakumar
AU - Han, Xianlin
AU - Young, Deanna M.
AU - Leone, Teresa C.
AU - Gross, Richard W.
AU - Lewandowski, E. Douglas
AU - Abel, E. Dale
AU - Kelly, Daniel P.
PY - 2008/7
Y1 - 2008/7
N2 - High-capacity mitochondrial ATP production is essential for normal function of the adult heart, and evidence is emerging that mitochondrial derangements occur in common myocardial diseases. Previous overexpression studies have shown that the inducible transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is capable of activating postnatal cardiac myocyte mitochondrial biogenesis. Recently, we generated mice deficient in PGC-1α (PGC-1α-/- mice), which survive with modestly blunted postnatal cardiac growth. To determine if PGC-1α is essential for normal cardiac energy metabolic capacity, mitochondrial function experiments were performed on saponin-permeabilized myocardial fibers from PGC-1α-/- mice. These experiments demonstrated reduced maximal (state 3) palmitoyl-L-carnitine respiration and increased maximal (state 3) pyruvate respiration in PGC-1α-/- mice compared with PGC-1α+/+ controls. ATP synthesis rates obtained during maximal (state 3) respiration in permeabilized myocardial fibers were reduced for PGC-1α-/- mice, whereas ATP produced per oxygen consumed (ATP/O), a measure of metabolic efficiency, was decreased by 58% for PGC-1α-/- fibers. Ex vivo isolated working heart experiments demonstrated that PGC-1α-/- mice exhibited lower cardiac power, reduced palmitate oxidation, and increased reliance on glucose oxidation, with the latter likely a compensatory response. 13C NMR revealed that hearts from PGC-1α-/- mice exhibited a limited capacity to recruit triglyceride as a source for lipid oxidation during β-adrenergic challenge. Consistent with reduced mitochondrial fatty acid oxidative enzyme gene expression, the total triglyceride content was greater in hearts of PGC-1α-/- mice relative to PGC-1α+/+ following a fast. Overall, these results demonstrate that PGC-1α is essential for the maintenance of maximal, efficient cardiac mitochondrial fatty acid oxidation, ATP synthesis, and myocardial lipid homeostasis.
AB - High-capacity mitochondrial ATP production is essential for normal function of the adult heart, and evidence is emerging that mitochondrial derangements occur in common myocardial diseases. Previous overexpression studies have shown that the inducible transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is capable of activating postnatal cardiac myocyte mitochondrial biogenesis. Recently, we generated mice deficient in PGC-1α (PGC-1α-/- mice), which survive with modestly blunted postnatal cardiac growth. To determine if PGC-1α is essential for normal cardiac energy metabolic capacity, mitochondrial function experiments were performed on saponin-permeabilized myocardial fibers from PGC-1α-/- mice. These experiments demonstrated reduced maximal (state 3) palmitoyl-L-carnitine respiration and increased maximal (state 3) pyruvate respiration in PGC-1α-/- mice compared with PGC-1α+/+ controls. ATP synthesis rates obtained during maximal (state 3) respiration in permeabilized myocardial fibers were reduced for PGC-1α-/- mice, whereas ATP produced per oxygen consumed (ATP/O), a measure of metabolic efficiency, was decreased by 58% for PGC-1α-/- fibers. Ex vivo isolated working heart experiments demonstrated that PGC-1α-/- mice exhibited lower cardiac power, reduced palmitate oxidation, and increased reliance on glucose oxidation, with the latter likely a compensatory response. 13C NMR revealed that hearts from PGC-1α-/- mice exhibited a limited capacity to recruit triglyceride as a source for lipid oxidation during β-adrenergic challenge. Consistent with reduced mitochondrial fatty acid oxidative enzyme gene expression, the total triglyceride content was greater in hearts of PGC-1α-/- mice relative to PGC-1α+/+ following a fast. Overall, these results demonstrate that PGC-1α is essential for the maintenance of maximal, efficient cardiac mitochondrial fatty acid oxidation, ATP synthesis, and myocardial lipid homeostasis.
KW - ATP
KW - Cardiac energetics
KW - Coactivator-1α
KW - Heart failure
KW - Left ventricular hypertrophy
KW - Nuclear receptors
KW - Peroxisome proliferator-activated receptor-γ
UR - http://www.scopus.com/inward/record.url?scp=49849085702&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00081.2008
DO - 10.1152/ajpheart.00081.2008
M3 - Article
C2 - 18487436
AN - SCOPUS:49849085702
SN - 0363-6135
VL - 295
SP - H185-H196
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 1
ER -