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.

中文翻译：

---

FoxO1是运动引起的生理性心肌肥大所必需的，而组成性活性PI3K则不需要

胰岛素样生长因子1受体（IGF1R）和磷酸肌醇3激酶p110a（PI3K）是运动诱发的生理性心肌肥大的关键调节剂，并在病理重塑和心力衰竭的实验模型中提供保护。叉头类O1（FoxO1）是一种转录因子，可在体外调节IGF1R / PI3K激活下游的心肌肥大，但其在体内生理肥大中的作用尚不清楚。我们产生了心肌细胞特异性FoxO1基因敲除（cKO）小鼠，并在基础条件和由1）游泳训练或2）组成性活性PI3K（caPI3K ^{Tg +}）。在基础条件下，与对照组（CON）同窝幼仔相比，雄性和雌性cKO小鼠表现出轻度的间质纤维化，但没有其他心脏病理迹象。响应运动训练，与未经训练的小鼠相比，雌性CON小鼠表现出以胫骨长度标准化的心重增加（〜21％）。运动诱发的肥大在cKO小鼠中变钝。运动可增加心脏Akt磷酸化和IGF1R表达，但在基因型之间可比。但是，在运动的cKO小鼠的心脏中发现了Foxo3a，Hsp70和自噬标记的差异。FoxO1的删除并没有减少雄性或雌性caPI3K ^{Tg +}小鼠的心脏肥大。caPI3K ^{Tg +}心脏中的心脏Akt和FoxO1蛋白表达显着降低小鼠，可能代表了慢性caPI3K的负反馈机制，并抵消了降低cKO中FoxO1的任何进一步作用。总之，FoxO1有助于运动引起的肥大。当考虑将FoxO1作为治疗患病心脏的靶标时，这具有重要意义。