title: Growth hormone secretagogues exert differential effects on skeletal muscle calcium homeostasis in male rats depending on the peptidyl/nonpeptidyl structure.
abstract: The orexigenic and anabolic effects induced by ghrelin and the synthetic GH secretagogues (GHSs) are thought to positively contribute to therapeutic approaches and the adjunct treatment of a number of diseases associated with muscle wasting such as cachexia and sarcopenia. However, many questions about the potential utility and safety of GHSs in both therapy and skeletal muscle function remain unanswered. By using fura-2 cytofluorimetric technique, we determined the acute effects of ghrelin, as well as of peptidyl and nonpeptidyl synthetic GHSs on calcium homeostasis, a critical biomarker of muscle function, in isolated tendon-to-tendon male rat skeletal muscle fibers. The synthetic nonpeptidyl GHSs, but not peptidyl ghrelin and hexarelin, were able to significantly increase resting cytosolic calcium [Ca²⁺]i. The nonpeptidyl GHS-induced [Ca²⁺]i increase was independent of GHS-receptor 1a but was antagonized by both thapsigargin/caffeine and cyclosporine A, indicating the involvement of the sarcoplasmic reticulum and mitochondria. Evaluation of the effects of a pseudopeptidyl GHS and a nonpeptidyl antagonist of the GHS-receptor 1a together with a drug-modeling study suggest the conclusion that the lipophilic nonpeptidyl structure of the tested compounds is the key chemical feature crucial for the GHS-induced calcium alterations in the skeletal muscle. Thus, synthetic GHSs can have different effects on skeletal muscle fibers depending on their molecular structures. The calcium homeostasis dysregulation specifically induced by the nonpeptidyl GHSs used in this study could potentially counteract the beneficial effects associated with these drugs in the treatment of muscle wasting of cachexia- or other age-related disorders.
authors.affiliation: Section of Pharmacology, Department of Pharmacy-Drug Sciences, University of Bari, Via Orabona, 4, Campus, I-70125 Bari, Italy. antonella.liantonio@uniba.it.
authors.forename: Antonella
authors.initials: A
authors.lastname: Liantonio
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gramegna
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Carbonara
authors.forename: Valeriana Teresa
authors.initials: VT
authors.lastname: Sblendorio
authors.forename: Sabata
authors.initials: S
authors.lastname: Pierno
authors.forename: Bodvaël
authors.initials: B
authors.lastname: Fraysse
authors.forename: Viviana
authors.initials: V
authors.lastname: Giannuzzi
authors.forename: Laura
authors.initials: L
authors.lastname: Rizzi
authors.forename: Antonio
authors.initials: A
authors.lastname: Torsello
authors.forename: Diana Conte
authors.initials: DC
authors.lastname: Camerino
mesh_terms: D000818:Animals; D019167:Appetite Stimulants / Q000009:adverse effects / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects*; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D054439:Ghrelin / Q000031:analogs & derivatives* / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000009:adverse effects / Q000494:pharmacology; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D054440:Receptors, Ghrelin / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013141:Spiro Compounds / Q000009:adverse effects / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D019167:Appetite Stimulants; D054439:Ghrelin; C571124:Ghsr1a protein, rat; D009842:Oligopeptides; D010880:Piperidines; D054440:Receptors, Ghrelin; D013141:Spiro Compounds; C086184:hexarelin; C102119:L 163255; D013006:Growth Hormone