| First Author | Weeks KL | Year | 2021 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 320 |
| Issue | 4 | Pages | H1470-H1485 |
| PubMed ID | 33577435 | Mgi Jnum | J:305039 |
| Mgi Id | MGI:6514248 | Doi | 10.1152/ajpheart.00838.2020 |
| Citation | Weeks KL, et al. (2021) FoxO1 is required for physiological cardiac hypertrophy induced by exercise but not by constitutively active PI3K. Am J Physiol Heart Circ Physiol 320(4):H1470-H1485 |
| abstractText | The insulin-like growth factor 1 receptor (IGF1R) and phosphoinositide 3-kinase p110a (PI3K) are critical regulators of exercise-induced physiological cardiac hypertrophy, and provide protection in experimental models of pathological remodeling and heart failure. Forkhead box class O1 (FoxO1) is a transcription factor which regulates cardiomyocyte hypertrophy downstream of IGF1R/PI3K activation in vitro, but its role in physiological hypertrophy in vivo was unknown. We generated cardiomyocyte-specific FoxO1 knockout (cKO) mice and assessed the phenotype under basal conditions and settings of physiological hypertrophy induced by 1) swim training, or 2) cardiac-specific transgenic expression of constitutively active PI3K (caPI3K(Tg+)). Under basal conditions, male and female cKO mice displayed mild interstitial fibrosis compared with control (CON) littermates, but no other signs of cardiac pathology were present. In response to exercise training, female CON mice displayed an increase (~21%) in heart weight normalized to tibia length vs untrained mice. Exercise-induced hypertrophy was blunted in cKO mice. Exercise increased cardiac Akt phosphorylation and IGF1R expression, but was comparable between genotypes. However, differences in Foxo3a, Hsp70 and autophagy markers were identified in hearts of exercised cKO mice. Deletion of FoxO1 did not reduce cardiac hypertrophy in male or female caPI3K(Tg+) mice. Cardiac Akt and FoxO1 protein expression were significantly reduced in hearts of caPI3K(Tg+) mice, which may represent a negative feedback mechanism from chronic caPI3K, and negate any further effect of reducing FoxO1 in the cKO. In summary, FoxO1 contributes to exercise-induced hypertrophy. This has important implications when considering FoxO1 as a target for treating the diseased heart. |
