Growth hormone secretagogues exert differential effects on skeletal muscle calcium homeostasis in male rats depending on the peptidyl/non-peptidyl structure

TheorexigenicandanaboliceffectsinducedbyghrelinandthesyntheticGHsecretagogues(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, manyquestionsaboutthepotentialutilityandsafetyofGHSsinboththerapyandskeletalmuscle functionremainunanswered.Byusingfura-2cytofluorimetrictechnique,wedeterminedtheacute effectsofghrelin,aswellasofpeptidylandnonpeptidylsyntheticGHSsoncalciumhomeostasis, a critical biomarker of muscle function, in isolated tendon-to-tendon male rat skeletal muscle fibers.ThesyntheticnonpeptidylGHSs,butnotpeptidylghrelinandhexarelin,wereabletosignificantlyincreaserestingcytosoliccalcium[Ca2]i.ThenonpeptidylGHS-induced[Ca2] iincrease was independent of GHS-receptor 1a but was antagonized by both thapsigargin/caffeine and cyclosporineA,indicatingtheinvolvementofthesarcoplasmicreticulumandmitochondria.EvaluationoftheeffectsofapseudopeptidylGHSandanonpeptidylantagonistoftheGHS-receptor 1a together with a drug-modeling study suggest the conclusion that the lipophilic nonpeptidyl structureofthetestedcompoundsisthekeychemicalfeaturecrucialfortheGHS-inducedcalcium alterationsintheskeletalmuscle.Thus,syntheticGHSscanhavedifferenteffectsonskeletalmuscle fibersdependingontheirmolecularstructures.Thecalciumhomeostasisdysregulationspecifically 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.