PGC-1 promotes cardiac mitochondrial biogenesis. PGC-1, a transcriptional coactivator, regulates mitochondrial function in tissues specialized for thermogenesis, such as brown adipose tissue. This study investigates whether PGC-1 controls mitochondrial biogenesis and energy production in the heart, a tissue specialized for high ATP production. PGC-1 gene expression is induced in the mouse heart after birth and in response to short-term fasting, conditions that increase cardiac mitochondrial energy production. Forced expression of PGC-1 in cardiac myocytes in culture induces the expression of nuclear and mitochondrial genes involved in multiple mitochondrial energy-transduction/energy-production pathways, increases mitochondrial number, and stimulates coupled respiration. Cardiac-specific overexpression of PGC-1 in transgenic mice results in uncontrolled mitochondrial proliferation in cardiac myocytes, leading to loss of sarcomeric structure and dilated cardiomyopathy. These results identify PGC-1 as a critical regulatory molecule in the control of cardiac mitochondrial number and function in response to energy demands. PGC-1 is shown to induce mitochondrial FAO cycle enzyme expression and mitochondrial biogenesis in cardiac myocytes in culture and in the heart of transgenic mice. In contrast to its action in noncardiac cell types, PGC-1 induces coupled mitochondrial respiration in cardiac myocytes consistent with the biogenesis of mitochondria capable of ATP production. PGC-1 promotes mitochondrial biogenesis in cardiac myocytes in culture. The results of the gene and protein expression studies shown in Figure 3 are indicative of a mitochondrial biogenic response to PGC-1 overexpression. PGC-1 induces mitochondrial biogenesis in cardiac myocytes. Forced expression of PGC-1 in neonatal cardiac myocytes increases oxygen consumption and coupled respiration. PGC-1 increases cardiac myocyte capacity for mitochondrial respiration. The effect of PGC-1 on cardiac myocyte UCP expression was delineated. PGC-1 overexpression decreased cardiac myocyte UCP-2 mRNA levels by approximately 60%, while increasing ATP synthase-β subunit mRNA levels threefold. Cardiac overexpression of PGC-1 in vivo in transgenic mice induces uncontrolled mitochondrial biogenesis. To evaluate the effect of forced PGC-1 expression in the intact postnatal heart in vivo, the cardiac α-MHC gene promoter was used to produce transgenic mice with high-level postnatal, cardiac-specific expression of PGC-1 (MHC-PGC-1 mice). MHC-PGC-1 transgenic mice from three independent lines (ages 1–5 weeks) exhibited high-level cardiac-specific transgene expression and increased mitochondrial DNA content compared with nontransgenic littermate controls. The transgenic mice of all three independent lines exhibited massive edema, increased heart size, and four-chamber enlargement consistent with a dilated cardiomyopathy. Histologic studies performed on left-ventricular tissue from the MHC-PGC-1PGC-1 promotes cardiac mitochondrial biogenesis. PGC-1, a transcriptional coactivator, regulates mitochondrial function in tissues specialized for thermogenesis, such as brown adipose tissue. This study investigates whether PGC-1 controls mitochondrial biogenesis and energy production in the heart, a tissue specialized for high ATP production. PGC-1 gene expression is induced in the mouse heart after birth and in response to short-term fasting, conditions that increase cardiac mitochondrial energy production. Forced expression of PGC-1 in cardiac myocytes in culture induces the expression of nuclear and mitochondrial genes involved in multiple mitochondrial energy-transduction/energy-production pathways, increases mitochondrial number, and stimulates coupled respiration. Cardiac-specific overexpression of PGC-1 in transgenic mice results in uncontrolled mitochondrial proliferation in cardiac myocytes, leading to loss of sarcomeric structure and dilated cardiomyopathy. These results identify PGC-1 as a critical regulatory molecule in the control of cardiac mitochondrial number and function in response to energy demands. PGC-1 is shown to induce mitochondrial FAO cycle enzyme expression and mitochondrial biogenesis in cardiac myocytes in culture and in the heart of transgenic mice. In contrast to its action in noncardiac cell types, PGC-1 induces coupled mitochondrial respiration in cardiac myocytes consistent with the biogenesis of mitochondria capable of ATP production. PGC-1 promotes mitochondrial biogenesis in cardiac myocytes in culture. The results of the gene and protein expression studies shown in Figure 3 are indicative of a mitochondrial biogenic response to PGC-1 overexpression. PGC-1 induces mitochondrial biogenesis in cardiac myocytes. Forced expression of PGC-1 in neonatal cardiac myocytes increases oxygen consumption and coupled respiration. PGC-1 increases cardiac myocyte capacity for mitochondrial respiration. The effect of PGC-1 on cardiac myocyte UCP expression was delineated. PGC-1 overexpression decreased cardiac myocyte UCP-2 mRNA levels by approximately 60%, while increasing ATP synthase-β subunit mRNA levels threefold. Cardiac overexpression of PGC-1 in vivo in transgenic mice induces uncontrolled mitochondrial biogenesis. To evaluate the effect of forced PGC-1 expression in the intact postnatal heart in vivo, the cardiac α-MHC gene promoter was used to produce transgenic mice with high-level postnatal, cardiac-specific expression of PGC-1 (MHC-PGC-1 mice). MHC-PGC-1 transgenic mice from three independent lines (ages 1–5 weeks) exhibited high-level cardiac-specific transgene expression and increased mitochondrial DNA content compared with nontransgenic littermate controls. The transgenic mice of all three independent lines exhibited massive edema, increased heart size, and four-chamber enlargement consistent with a dilated cardiomyopathy. Histologic studies performed on left-ventricular tissue from the MHC-PGC-1