Peptidic and Nonpeptidic Growth Hormone Secretagogues exert a protective effect on mitochondrial parameters analysed in a rat model of cachexia

Background and aims: Cachexia and muscle atrophy are common derivations of cancer and chemotherapy treatments (cisplatin). Growth Hormone Secretagogues (GHSs) are synthetic peptidic and nonpeptidic molecules, able to stimulate Growth Hormone secretion and to target a specific receptor in skeletal muscle counteracting cachexia. We report the effects of GHSs on skeletal muscle mitochondrial biogenesis and dynamics in a rat model of cisplatin induced cachexia. Methods: Cachexia was induced in adult rats by intraperitoneal injection of cisplatin (1 mg/kg) once daily for 3 days. The treatment with GHSs was hexarelin, 160 μg/Kg and JMV2894, 320 μg/Kg, ip, and b.i.d, for 5 days. Results: We measured in rat tibialis anterior of cisplatin treated group, a decrease of the level of mtDNA, PGC-1α and TFAM (proteins involved in mitochondrial biogenesis), PRX3 and SOD2 (antioxidant mitochondrial enzymes) and an increase of the oxidized total cellular PRXs which suggest an increase of ROS damages. GHSs treatment increased mtDNA, PGC-1α and TFAM, PRX3 and SOD2 level while reduced the oxidized total cellular PRXs. The MFN2 and Drp1 proteins level increased with cisplatin administration, whereas it decreased after GHSs treatment. These results demonstrated that cisplatin treatment depresses several parameters linked to mitochondrial biogenesis and integrity and that the GHSs administration prevents these alterations. It is involved in the disease the activation of proteolysis due to AKT and FoxO3a dephosphorylation, whereas PGC-1α is able to inhibit the transcriptional activity of FoxO3a, suppressing atrogenes expression and protein degradation. In particular, GHSs stimulated the phosphorylation of AKT and FoxO3a, thus inducing a recovery of skeletal muscle mass. In addition, the here reported increase of PGC-1α prevents the activation of atrogenes by blocking the FoxO3a function. Conclusions: These data indicate that treatment with GHSs exert a muscle protective effect in cisplatin-induced model of cachexia and may be a therapeutic promising tool for supportive care in cachexia.