| First Author | Tuomainen T | Year | 2022 |
| Journal | Cells | Volume | 11 |
| Issue | 19 | PubMed ID | 36230906 |
| Mgi Jnum | J:330184 | Mgi Id | MGI:7365517 |
| Doi | 10.3390/cells11192944 | Citation | Tuomainen T, et al. (2022) PGC-1alpha4 Interacts with REST to Upregulate Neuronal Genes and Augment Energy Consumption in Developing Cardiomyocytes. Cells 11(19) |
| abstractText | Transcriptional coactivator PGC-1alpha is a main regulator of cardiac energy metabolism. In addition to canonical PGC-1alpha1, other PGC-1alpha isoforms have been found to exert specific biological functions in a variety of tissues. We investigated the expression patterns and the biological effects of the non-canonical isoforms in the heart. We used RNA sequencing data to identify the expression patterns of PGC-1alpha isoforms in the heart. To evaluate the biological effects of the alternative isoform expression, we generated a transgenic mouse with cardiac-specific overexpression of PGC-1alpha4 and analysed the cardiac phenotype with a wide spectrum of physiological and biophysical tools. Our results show that non-canonical isoforms are expressed in the heart, and that the main variant PGC-1alpha4 is induced by beta-adrenergic signalling in adult cardiomyocytes. Cardiomyocyte specific PGC-1alpha4 overexpression in mice relieves the RE1-Silencing Transcription factor (REST)-mediated suppression of neuronal genes during foetal heart development. The resulting de-repression of REST target genes induces a cardiac phenotype with increased cellular energy consumption, resulting in postnatal dilated cardiomyopathy. These results propose a new concept for actions of the PGC-1alpha protein family where activation of the Pgc-1alpha gene, through its isoforms, induces a phenotype with concurrent supply and demand for cellular energy. These data highlight the biological roles of the different PGC-1alpha isoforms, which should be considered when future therapies are developed. |
