The role of unacylated ghrelin on age-associated progressive muscle weakness and cachexia elicited by cancer

Project Summary/Abstract
Skeletal muscle weakness is a hallmark of aging and cancer cachexia that significantly affect individual
healthspans and quality of life. Despite the clinical significance, no pharmacological therapies are currently
available to mitigate muscle atrophy and weakness. The goal of this project is to test the ability of a novel and
promising pharmacological intervention, unacylated ghrelin, to delay skeletal muscle weakness and loss
of muscle mass in aging and in cancer cachexia. Ghrelin is a hormone that increases appetite when the
acylated ghrelin (AG) binds to its receptor in the brain, growth hormone secretagogue receptor-1a (GHSR1a).
An acute rise in AG increases lean mass in wasting conditions, but a concurrent increase in adiposity and
decreased sensitivity in GHSR1a receptor lead to atrophy and contractile dysfunction. In contrast, recent studies
show a direct beneficial effect of the unacylated form of ghrelin (UnAG) on muscle, independent of GHSR1a
activation. Incubating myoblast with UnAG increases differentiation and fusion into myotubes, and inhibited
glucocorticoid-induced muscle atrophy and proteolytic markers. During a 2-day fasting and 14-day denervation,
a chronic increase in circulating UnAG using a genetic modification prevented skeletal muscle atrophy
independent of activation of the growth hormone/IGF-1 axis via GHSR1a. The goal of this proposal is to test the
ability of UnAG to mitigate loss of muscle mass and weakness in two distinct degenerative conditions-sarcopenia
and cancer cachexia. The following aims are proposed: Aim 1: To determine whether UnAG prevents neurogenic
atrophy with aging by altering rates of protein synthesis and degradation in muscle. Aim 2: To determine whether
UnAG prevents contractile dysfunction with aging through modulations of calcium handling and sensitivity. Aim
3: To determine whether UnAG prevents a rapid wasting and contractile dysfunction in cancer cachexia. In order
to understand the molecular mechanisms of UnAG on skeletal muscle cells, I will learn and perform state-of-the-
art molecular biology and integrative physiology techniques to assess in vivo protein turnover rate and calcium
handling and sensitivity of myofilaments (intracellular calcium transient and uptake). If my results support the
hypothesis, clinical trials may be warranted. UnAG and its synthetic peptides have excellent safety profiles in
humans and animals with null association to cancer cell growth.
The principal investigator (PI) of this grant is a postdoctoral fellow under the mentorship of Dr. Van Remmen
at Oklahoma Medical Research Foundation. The PI will learn state-of-the-art molecular biology and integrative
physiology techniques from his co-mentors Drs. Benjamin Miller and Susan Brooks, respectively. These
techniques will be critical in the PI’s independent laboratory and boost his scientific career. The PI’s primary
mentor, Dr. Holly Van Remmen, will train him the expertise in redox biology and share her experience and
success in aging research. Dr. Van Remmen will monitor overall progress of the project and the PI’s career
development during the mentored phase and ensure his secure transition toward independence.

Grant Number: 5R00AG064143-05
NIH Institute/Center: NIH
Principal Investigator: Bumsoo Ahn