All ETDs from UAB

Advisory Committee Chair

Stuart J Frank

Advisory Committee Members

Shannon Bailey

Anath Shalev

Victor J Thannickal

Martin E Young

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Growth hormone (GH) signaling plays a critical role in postnatal development and the details of its release, regulation, and influence on the development of a number of organs has been well studied. GH is released from the anterior pituitary in a pulsatile fashion with pulse amplitude being greater at night than during the day in a number of species, including humans. Once in circulation, GH binds to the GH receptor (GHR) on target tissues throughout the body altering gene expression and stimulating the local production of insulin-like growth factor 1 (IGF-1). IGF-1 primarily acts in an autocrine and paracrine fashion. Interestingly, after roughly a century of GH research, comparative tissue sensitivity to a GH pulse has yet to be described. The work herein encompassed provides a comparative description of GH sensitivity and responsiveness of five key metabolic tissues in mice ( heart, liver, kidney, epidydymal white adipose tissue, and skeletal muscle). We then home in on the heart and the influence of circadian rhythms. It is well known that a number of mechanisms and pathologies affecting the heart occur in a time-of-day dependent manner including normal nightly dips in blood pressure and increases in GH secretion and increased incidence of acute myocardial infarctions in the early mornings; these processes are influenced by the circadian clock. The cardiomyocyte-specific BMAL1 knockout (CBK) mice have a functional central clock in the suprachiasmatic nucleus and functional peripheral clocks everywhere but cardiomyocytes. These animals experience altered metabolic processes, including insulin sensitivity, early age onset heart failure, and early mortality. It has also been suggested that the cardiomyocyte circadian clock influences GH related signaling processes. Here, we describe altered time-of-day dependent GH sensitivity, and other signs of increased GH signaling in CBK hearts including elevated igf-1 gene expression. We also introduce and characterize the cardiomyocyte-specific BMAL1(-/-) IGF-1(-/+) (CBKI)- Cre(+) mouse in an attempt to partially rescue the cardiac hypertrophy phenotype of the CBK mice.

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