Unacylated ghrelin ameliorates muscle atrophy and contractile dysfunction in age‐associated loss of muscle mass and function

Abstract

Sarcopenia, the progressive loss of muscle mass and dysfunction, universally affects the elderly and is closely associated with frailty and reduced quality of life. Despite the inevitable consequences of sarcopenia and its relevance to healthspan, no pharmacological therapies are currently available. Ghrelin is a gut-released hormone that increases appetite and body weight through acylation (acyl ghrelin, AG), which binds to its receptors (GHSR1a) in the brain. Growing studies demonstrate that AG and “unacyl” ghrelin (UnAG) both have direct impacts on proliferation independent of GHSR1a. Neuronal precursor cells and myoblast incubated with UnAG increases proliferation and protein synthesis rate by promoting differentiation and fusion. Thus, we hypothesized that UnAG ameliorates neurogenic atrophy and contractile dysfunction in aged skeletal muscle. Young (4 mo.) and old (18 mo.) female mice were treated with saline or UnAG. UnAG (100 µg/kg/day) via osmotic pump for 9-10 months. We assessed in vitro contractile properties of isolated extensor digitorum longus (EDL). UnAG treatment significantly increased terminal serum UnAG levels in the old animals. In contrast to previous studies using AG, UnAG did not affect food consumption or body weight. Muscle mass of gastrocnemius and quadriceps were ~20-30% decreased in old mice, but UnAG ameliorated the atrophy by 15-30% for both muscles. Specific force (force per cross-sectional are) of isolated EDL muscle was diminished by ~30% in Sod1KO, but UnAG restored the force deficit by ~80% in the KO mice. We find that upregulation of protein kinase A (PKA) and hyper-phosphorylation of FoxO3a signaling pathways may contribute to the protection. RNA-seq analysis further revealed that UnAG shifted mRNA expression of 366 genes towards younger states that are differentially regulated in old mice. Our data show a direct role of UnAG on sarcopenia independent of changes of food consumption or body weight, implicating UnAG as a potential therapeutic strategy that can enhance quality of life and healthspan of rapidly growing elderly population.