Transcriptional coactivator PGC-1α controls the energy state and contractile function of cardiac muscle

Abstract

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.

Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-γ coactivator 1α

“…Earlier work had shown that hearts of mice lacking PGC-1␣ have reduced expression of many mitochondrial genes, a significant defect in ATP balance, and a blunted capacity to increase work output in response to an inotropic stimulus (26). However, the ability of hearts from mice mutant in PGC-1␣ to withstand a challenge in the form of pressure overload, such as seen in patients with hypertension or aortic stenosis, was unknown.…”

“…A number of gain-of-function assays have shown both in vitro and in vivo that PGC-1␣ activates most genes of mitochondrial biology and stimulates both fatty acid oxidation and oxidative respiration in cardiac tissue (22)(23)(24)(25). Conversely, we have recently shown that ablation of the PGC-1␣ gene caused important deficiencies in cardiac energy reserves and function (26). In the absence of PGC-1␣, the expression of mitochondrial genes in the heart was suppressed, the activities of mitochondrial enzymes were aberrant, and ATP production was blunted.…”

Nuclear receptors, mitochondria and lipid metabolism

“…The activities are most notable in highly metabolic tissues, such as brown adipose tissue, heart, skeletal muscle, liver and the CNS, where PGC-1a regulates the central characteristics of these differentiated tissues: thermogenesis, contractile force, oxidative fiber types, gluconeogenesis and beta-oxidation, and emerging roles in the CNS such as ROS adaptation and apoptosis. (Puigserver et al 1998;Herzig et al 2001;Lin et al 2002;Puigserver et al 2003;Rhee et al 2003;Arany et al 2005;St-Pierre et al 2006;Handschin et al 2007). While named for its interaction with PPARγ, many of these PGC-1-dependent adaptations appear to be largely dependent on ERRs and other metabolic transcription factors that are independent of PPAR/RXR Rhee et al 2003;Schilling et al 2006;Alaynick et al 2007;Huss et al 2007;Villena et al 2007).…”

Age‐dependent electrocardiographic changes in Pgc‐1β deficient murine hearts

“…They interact with cardiomyocyte nuclear receptor factor‐1, estrogen related receptor‐α and peroxisome proliferator‐activated receptor‐α in increasing mitochondrial biogenesis 8. They also upregulate expression of nuclear and/or mitochondrial‐encoded mitochondrial proteins involved in fatty acid β‐oxidation, the tricarboxylic acid cycle and electron transport 9. PGC‐1 protein expression and the corresponding mitochondrial activity, is coordinated with several upstream stimuli reflecting the heart's energetic demand 10.…”

“…Cardiac phenotypes of mice lacking individual members of the PGC‐1 family are less severe. Pgc‐1 α deficient murine hearts show normal baseline contractile function but develop cardiac failure following increased afterload 9. Studies on Pgc ‐1β deficient hearts are more limited, but nevertheless report normal baseline cardiac function despite their reduced mitochondrial content, but blunted heart rate responses following adrenergic stimulation 14.…”