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Skeletal muscle loss is one of the main characteristics of cachexia that significantly contributes to the functional muscle impairment. Calcium\u2010dependent signaling pathways are believed to play an important role in skeletal muscle decline observed in cachexia, but whether intracellular calcium homeostasis is affected in this situation remains uncertain. Growth hormone secretagogues (GHS), a family of synthetic agonists of ghrelin receptor (GHS\u2010R1a), are being developed as a therapeutic option for cancer cachexia syndrome; however, the exact mechanism by which GHS interfere with skeletal muscle is not fully understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>By a multidisciplinary approach ranging from cytofluorometry and electrophysiology to gene expression and histology, we characterized the calcium homeostasis in fast\u2010twitch extensor digitorum longus (EDL) muscle of adult rats with cisplatin\u2010induced cachexia and established the potential beneficial effects of two GHS (hexarelin and JMV2894) at this level. Additionally, <jats:italic>in vivo<\/jats:italic> measures of grip strength and of ultrasonography recordings allowed us to evaluate the functional impact of GHS therapeutic intervention.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cisplatin\u2010treated EDL muscle fibres were characterized by a ~18% significant reduction of the muscle weight and fibre diameter together with an up\u2010regulation of <jats:italic>atrogin1<\/jats:italic>\/<jats:italic>Murf\u20101<\/jats:italic> genes and a down\u2010regulation of <jats:italic>Pgc1\u2010a<\/jats:italic> gene, all indexes of muscle atrophy, and by a two\u2010fold increase in resting intracellular calcium, [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>, compared with control rats. Moreover, the amplitude of the calcium transient induced by caffeine or depolarizing high potassium solution as well as the store\u2010operated calcium entry were ~50% significantly reduced in cisplatin\u2010treated rats. Calcium homeostasis dysregulation parallels with changes of functional <jats:italic>ex vivo<\/jats:italic> (excitability and resting macroscopic conductance) and <jats:italic>in vivo<\/jats:italic> (forelimb force and muscle volume) outcomes in cachectic animals. Administration of hexarelin or JMV2894 markedly reduced the cisplatin\u2010induced alteration of calcium homeostasis by both common as well as drug\u2010specific mechanisms of action. This effect correlated with muscle function preservation as well as amelioration of various atrophic indexes, thus supporting the functional impact of GHS activity on calcium homeostasis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings provide a direct evidence that a dysregulation of calcium homeostasis plays a key role in cisplatin\u2010induced model of cachexia gaining insight into the etiopathogenesis of this form of muscle wasting. Furthermore, our demonstration that GHS administration efficaciously prevents cisplatin\u2010induced calcium homeostasis alteration contributes to elucidate the mechanism of action through which GHS could potentially ameliorate chemotherapy\u2010associated cachexia.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12185","type":"journal-article","created":{"date-parts":[[2017,3,10]],"date-time":"2017-03-10T15:02:57Z","timestamp":1489158177000},"page":"386-404","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Growth hormone secretagogues prevent dysregulation of skeletal muscle calcium homeostasis in a rat model of cisplatin\u2010induced cachexia"],"prefix":"10.1002","volume":"8","author":[{"given":"Elena","family":"Conte","sequence":"first","affiliation":[{"name":"Department of Pharmacy \u2013 Drug Sciences University of Bari  Via Orabona 4 70125 Bari 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