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.

Growth hormone secretagogues prevent dysregulation of skeletal muscle calcium homeostasis in a rat model of cisplatin‐induced cachexia

“…Indeed, these results could be explained by postulating the ability of synthetic GHS to interact not only with the GHS‐R1a but also with some other still unknown receptors. Nevertheless, the different molecular structure of the GHS under investigation in our study could account for the different efficacy on caffeine responsiveness, because, as we previously reported, GHS differently affect skeletal muscle calcium homeostasis in dependence on their peptidyl or non‐peptidyl structure. In contrast to the peptidyl structure of hexarelin, JMV2894 is a peptidomimetic compound containing the 1,2,4‐triazole scaffold as mimetic of the cis‐configuration of amide .…”

“…Additionally, a direct action at the level the adipose tissue and skeletal muscle are thought to potentially mediate some GHS effects. In this regard, we have previously demonstrated that GHS can differently affect skeletal muscle functionality through regulation of intracellular calcium in dependence of their molecular structure …”

“…In this regard, we have previously demonstrated that GHS can differently affect skeletal muscle functionality through regulation of intracellular calcium in dependence of their molecular structure. 27,28 Animal models of cachexia are usually obtained by cancerinduced or chemotherapy-induced muscle atrophy. 29,30 Cisplatin, a platinum-based anticancer drug, is one of the most widely used and potent chemotherapeutic agent, effective against several solid tumours.…”

Growth hormone secretagogues hexarelin and JMV2894 protect skeletal muscle from mitochondrial damages in a rat model of cisplatin-induced cachexia

“…The non peptidic agonist JMV2894, was often more effective than the peptidic hexarelin in preventing cisplatin-induced alterations of cell metabolism. Similarly, JMV2894 was more effective in restoring calcium homeostasis and the expression of some calcium-related proteins 18,60 .…”

Growth Hormone Secretagogues and the Regulation of Calcium Signaling in Muscle

“…On the other hand, the binding sites mediating the GH-releasing and orexigenic effects of GHS are apparently very permissive, since very different peptides (from hexa- to tripeptides) have shown identical activity [63]. Some non-peptidyl GHS can affect Ca 2+ homeostasis, increasing the resting intracellular (Ca 2+ ) differently from hexarelin and other peptidyl compounds in skeletal muscle fibers [64]. This activity could be independent of the GHS-R1a activation, as demonstrated by the use of a specific competitive antagonist of the GHS-R1a, the D-Lys-GHRP-6 [65].…”