Cardiac-Specific Disruption of GH Receptor Alters Glucose Homeostasis While Maintaining Normal Cardiac Performance in Adult Male Mice

Abstract

GH is considered necessary for the proper development and maintenance of several tissues, including the heart. Studies conducted in both GH receptor null and bovine GH transgenic mice have demonstrated specific cardiac structural and functional changes. In each of these mouse lines, however, GH-induced signaling is altered systemically, being decreased in GH receptor null mice and increased in bovine GH transgenic mice. Therefore, to clarify the direct effects GH has on cardiac tissue, we developed a tamoxifen-inducible, cardiac-specific GHR disrupted (iC-GHRKO) mouse line. Cardiac GH receptor was disrupted in 4-month-old iC-GHRKO mice to avoid developmental effects due to perinatal GHR gene disruption. Surprisingly, iC-GHRKO mice showed no difference vs controls in baseline or postdobutamine stress test echocardiography measurements, nor did iC-GHRKO mice show differences in longitudinal systolic blood pressure measurements. Interestingly, iC-GHRKO mice had decreased fat mass and improved insulin sensitivity at 6.5 months of age. By 12.5 months of age, however, iC-GHRKO mice no longer had significant decreases in fat mass and had developed glucose intolerance and insulin resistance. Furthermore, investigation via immunoblot analysis demonstrated that iC-GHRKO mice had appreciably decreased insulin stimulated Akt phosphorylation, specifically in heart and liver, but not in epididymal white adipose tissue. These changes were accompanied by a decrease in circulating IGF-1 levels in 12.5-month-old iC-GHRKO mice. These data indicate that whereas the disruption of cardiomyocyte GH-induced signaling in adult mice does not affect cardiac function, it does play a role in systemic glucose homeostasis, in part through modulation of circulating IGF-1.

Identifying Protein–metabolite Networks Associated with COPD Phenotypes

“…Patients with COPD often show signs of muscle wasting as well as a shift from slow to fast-twitch muscle fibers, therefore, a change in growth hormone receptor expression could be expected [33]. Additionally, mouse models with growth hormone receptor knock-out show similar phenotypes to COPD patients such as impaired glucose tolerance [34], decreased heart function [35], and reduced muscle mass [36]. Growth hormone receptor expression can also decline as people age [37,38], especially after age 60.…”

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

“…To clarify the direct effects of GHR on cardiac tissue, our laboratory generated a tamoxifen-inducible cardiac-specific GHR disrupted (iC-GHRKO) mouse line at 4-month-old (309,310). No difference in baseline or in postdobutamine stress test echocardiography measurements or longitudinal systolic blood pressure measurements were found when compared with controls.…”

The Somatotropic Axis in Human Aging: Framework for the Current State of Knowledge and Future Research

“…However, alterations in GH signaling are also accompanied by concurrent changes in IGF-1 and insulin levels. This relationship has made it challenging to characterize the independent contribution of GH to aging and diseases of aging, though recent generation of animal models with extrahepatic targeted deletion of GH receptors (GHR) represent a significant step forward in overcoming these limitations to better clarify the role of GH (Jara et al, 2016; List et al, 2015). …”

“…On the other hand, Lewis dwarf rats, which have GH and IGF-1 deficiency, have increased incidence of stroke and arterial stress (Csiszar et al, 2008; Ungvari and Csiszar, 2012). However, because these models cannot distinguish from concomitant changes in circulating IGF-1, a model was generated with targeted disruption of GHR in cardiomyocytes (Jara et al, 2016); yet, no alteration in cardiac performance was observed in this model. In contrast, cardiac specific deletion of IGF-1R in adult mice was shown to impair diastolic function, while adult onset IGF-1 deficiency mice demonstrated multiple impairments in cardiovascular function (Bailey-Downs et al, 2012; Li et al, 2008).…”