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

Giuseppe Sirago,Jean Martinez,Flavio Fracasso,Palmiro Cantatore,Angela Maria Serena Lezza,Elena Conte,Laura Rizzi,Vito Pesce,Antonio Torsello,Giulia Maria Camerino,Antonella Cormio,Antonella Liantonio,Adriano Fonzino,Jean-Alain Fehrentz,Clara Musicco

doi:10.1038/s41598-017-13504-y

Abstract

Chemotherapy can cause cachexia, which consists of weight loss associated with muscle atrophy. The exact mechanisms underlying this skeletal muscle toxicity are largely unknown and co-therapies to attenuate chemotherapy-induced side effects are lacking. By using a rat model of cisplatin-induced cachexia, we here characterized the mitochondrial homeostasis in tibialis anterior cachectic muscle and evaluated the potential beneficial effects of the growth hormone secretagogues (GHS) hexarelin and JMV2894 in this setting. We found that cisplatin treatment caused a decrease in mitochondrial biogenesis (PGC-1α, NRF-1, TFAM, mtDNA, ND1), mitochondrial mass (Porin and Citrate synthase activity) and fusion index (MFN2, Drp1), together with changes in the expression of autophagy-related genes (AKT/FoxO pathway, Atg1, Beclin1, LC3AII, p62) and enhanced ROS production (PRX III, MnSOD). Importantly, JMV2894 and hexarelin are capable to antagonize this chemotherapy-induced mitochondrial dysfunction. Thus, our findings reveal a key-role played by mitochondria in the mechanism responsible for GHS beneficial effects in skeletal muscle, strongly indicating that targeting mitochondrial dysfunction might be a promising area of research in developing therapeutic strategies to prevent or limit muscle wasting in cachexia.

Highlights

Chemotherapy can cause cachexia, which consists of weight loss associated with muscle atrophy
According to the multiple actions proposed for ghrelin and GHS11, we demonstrated that administration of JMV2894, a novel peptidomimetic growth hormone secretagogues (GHS), and hexarelin, a well-known synthetic hexapeptide, antagonized cisplatin-induced muscle wasting
The reduction in body weight was associated with a significant decrease in cumulative food intake in cisplatin-treated rats, which was partially antagonized by GHS administration[18]

Summary

Introduction

Chemotherapy can cause cachexia, which consists of weight loss associated with muscle atrophy. By using a rat model of cisplatin-induced cachexia, we here characterized the mitochondrial homeostasis in tibialis anterior cachectic muscle and evaluated the potential beneficial effects of the growth hormone secretagogues (GHS) hexarelin and JMV2894 in this setting. A multimodal approach with nutritional support, moderate exercise and treatment with corticosteroids and progestational drugs is currently proposed for cachectic syndromes[4,5] These treatments have not proven to be clinically effective and there is a pressing need for newer clinical approaches to cachexia. Drug has been limited because of its short half-life and low plasma stability[7,8] For these reasons, several synthetic growth hormone secretagogues (GHS) have been developed and are studied for cachexia treatment[9,10,11]. A better knowledge of the mechanisms of action of GHS in cachexia is needed, since GHS compounds are presently under consideration by the European Medicine Agency for approval to be introduced into clinical practice for treatment of cachexia[12]

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Conclusion