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

• Published in: Scientific reports 2017-10, Vol.7 (1), p.13017-14, Article 13017
• Main Authors: Sirago, Giuseppe, Conte, Elena, Fracasso, Flavio, Cormio, Antonella, Fehrentz, Jean-Alain, Martinez, Jean, Musicco, Clara, Camerino, Giulia Maria, Fonzino, Adriano, Rizzi, Laura, Torsello, Antonio, Lezza, Angela Maria Serena, Liantonio, Antonella, Cantatore, Palmiro, Pesce, Vito
• Format: Article
• Language: English
• Subjects: 38; 38/1; 38/22; 38/77; 631/80/642/333; 692/4017; AKT protein; Animals; Atrophy; Autophagy; Autophagy - drug effects; Biochemistry, Molecular Biology; Biomarkers - metabolism; Body Weight - drug effects; Cachexia; Cachexia - chemically induced; Cachexia - pathology; Chemotherapy; Cisplatin; Cisplatin - adverse effects; Citrate synthase; Disease Models, Animal; Forkhead Box Protein O3 - metabolism; Forkhead protein; Growth Hormone - administration & dosage; Growth Hormone - pharmacology; Growth hormones; Homeostasis; Humanities and Social Sciences; Indoles - pharmacology; Life Sciences; Male; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial DNA; Mitochondrial Dynamics - drug effects; Molecular biology; multidisciplinary; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Musculoskeletal system; Oligopeptides - pharmacology; Organ Size - drug effects; Organelle Biogenesis; Oxidative Stress - drug effects; Phagocytosis; Phosphorylation - drug effects; Piperidines - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Rats; Science; Science (multidisciplinary); Secretagogues - administration & dosage; Secretagogues - pharmacology; Skeletal muscle; Superoxide dismutase; Toxicity; Triazoles - pharmacology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-13504-y

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.