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

Project Summary/Abstract
Skeletal muscle weakness is a hallmark of aging and cancer cachexia with significant impacts on individual
healthspan and quality of life. Despite the clinical significance, no pharmacological therapies are currently
available to attenuate muscle atrophy and weakness in the elderly and in patients with cancer cachexia. 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 binds to its receptor in the brain, growth
hormone secretagogue receptor-1a (GHSR1a). An acute rise in acylated ghrelin 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 ghrelin
on muscle, independent of GHSR1a activation. Incubating myoblast with unacylated ghrelin increases
differentiation and fusion into myotubes, and inhibited glucocorticoid-induced muscle atrophy and proteolytic
markers. An increase in unacylated ghrelin protected skeletal muscle from denervation-induced atrophy.
Therefore, the goal of this proposal is to test the ability of unacylated ghrelin 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 unacylated ghrelin prevents neurogenic atrophy with aging by altering
rates of protein synthesis and degradation in muscle. Aim 2: To determine whether unacylated ghrelin prevents
contractile dysfunction with aging through modulations of calcium handling and sensitivity. Aim 3: To determine
whether unacylated ghrelin prevents a rapid wasting and contractile dysfunction in cancer cachexia. In order to
understand the molecular mechanisms of unacylated ghrelin in skeletal muscle cells, member of my laboratory
will 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. If the results support our hypothesis, clinical
trials will be warranted. Unacylated ghrelin and its synthetic peptides have excellent safety profiles in humans
and animals with null association to cancer cell growth.

Grant Number: 3R00AG064143-05S1
NIH Institute/Center: NIH
Principal Investigator: Bumsoo Ahn