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

Abstract

Heart failure is accompanied by important defects in metabolism. The transcriptional coactivator peroxisome proliferator-activated receptor-␥ coactivator 1␣ (PGC-1␣) is a powerful regulator of mitochondrial biology and metabolism. PGC-1␣ and numerous genes regulated by PGC-1␣ are repressed in models of cardiac stress, such as that generated by transverse aortic constriction (TAC). This finding has suggested that PGC-1␣ repression may contribute to the maladaptive response of the heart to chronic hemodynamic loads. We show here that TAC in mice genetically engineered to lack PGC-1␣ leads to accelerated cardiac dysfunction, which is accompanied by signs of significant clinical heart failure. Treating cardiac cells in tissue culture with the catecholamine epinephrine leads to repression of PGC-1␣ and many of its target genes, recapitulating the findings in vivo in response to TAC. Importantly, introduction of ectopic PGC-1␣ can reverse the repression of most of these genes by epinephrine. Together, these data indicate that endogenous PGC-1␣ serves a cardioprotective function and suggest that repression of PGC-1␣ significantly contributes to the development of heart failure. Moreover, the data suggest that elevating PGC-1␣ activity may have therapeutic potential in the treatment of heart failure.cardiac metabolism ͉ mitochondria ͉ transcription

Gene expression-based screening identifies microtubule inhibitors as inducers of PGC-1α and oxidative phosphorylation

“…The induction of PGC-1␣ in skeletal muscle by genetic means improves angiogenesis and recovery from ischemia (41), blocks the atrophy triggered by denervation (21), and improves indices of muscle damage in a model of Duchenne's muscular dystrophy (22). PGC-1␣ may also have important cardioprotective and neuroprotective effects (13)(14)(15). Simultaneous induction of PGC-1␣ in all tissues in the body may harbor some side effects, such as induction of gluconeogenesis in the liver (11,12).…”

“…PGC-1␣ Ϫ/Ϫ mice are prone to several neurodegenerative diseases (13), suggesting a neuroprotective role for PGC-1␣. The same mice also have a strong predisposition to cardiac failure (14,15), and PGC-1␣ levels decline in a number of rodent models of heart dysfunction (16)(17)(18)(19)(20), suggesting a cardioprotective role for PGC-1␣ as well. Transgenic expression of PGC-1␣ in skeletal muscle protects from the atrophy associated with denervation, a model for ALS (21).…”

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

“…Lack of either PGC-1 or PGC-1 promotes heart failure under stress conditions while a PGC-1β cardiac deficiency combined with a global PGC-1α gene ablation is lethal shortly after birth as those hearts are unable to mature [115][116][117][118]. Inversely, cardiac PGC-1 overexpression causes disturbances in the sarcomere structure leading to dilated cardiomyopathy [119].…”

Tom70 serves as a molecular switch to determine pathological cardiac hypertrophy

“…Heart failure models were established through the administration of ISO to Sprague Dawley (SD, male, 180-200 g) rats and by performing transverse aortic constriction in mice, as previously reported [12,31]. Animal groupings and randomization were performed to ensure a balanced distribution of animals across all the study groups.…”