JMV2894, a novel growth hormone secretagogue, accelerates body mass recovery in an experimental model of cachexia

Abstract

Oncologic patients subjected to chemotherapy frequently present aphagia, malnutrition, and cachexia. The purpose of this study was to investigate whether selected growth hormone secretagogues including hexarelin, JMV2894 and JMV2951 could antagonize body weight loss and wasting induced by cisplatin administration in rats. The three growth hormone secretagogues behaved as full agonists of the growth hormone secretagogues receptor both in terms of ability to stimulate calcium mobilization in Chinese hamster ovary cells and stimulation of growth hormone release in neonatal rats. Adult rats were (i) treated with vehicle throughout (controls), or (ii) treated with cisplatin (days 1-3) and a growth hormone secretagogues or vehicle, (days 1-12). Body weight and food consumption were measured daily. Although all growth hormone secretagogues caused initial transient acute increases in food intake, the total amount of food eaten by controls and growth hormone secretagogues treated groups over the 12 experimental days was not significantly different. All groups pre-treated with cisplatin lost up to 5-10 % body weight in the first 4 days; they subsequently gained weight at a rate comparable with controls. Interestingly, rats which received JMV2894 demonstrated a faster gain in body weight than any other growth hormone secretagogues treated group and at the end of the protocol reached a weight similar to that of controls. JMV2894 did not stimulate perirenal and epididymal fat accumulation but reduced MuRF mRNA levels in skeletal muscles. In conclusion, our findings demonstrate that JMV2894 antagonizes cisplatin induced weight loss in rats and may prove useful in antagonizing cachexia associated with cancer and chemotherapy in humans.

Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies

“…Muscle atrophy F-Box (MAFbx)/atrogin-1 and muscle ring-finger-1 (MuRF-1), are two muscle-specific E3 ubiquitin ligases that are increased in skeletal muscle under atrophy-inducing conditions and considered markers for muscle atrophy [14,15]. Cisplatin-treated animals develop significant muscle atrophy and weakness followed by an increased expression of the ubiquitin ligases MAFbx/atrogin-1 and MuRF-1 systems [7][8][9]. This activation is partially due to dephosphorylation of the transcriptional factor Forkhead boxO (FoxO3a) [16], which is in turn regulated by the pivotal mediator Akt and regulates genes coding for the autophagy pathway contributing to the degradation of muscle proteins, finally promoting atrophy [17].…”

“…Reportedly, GHS enhance GH secretion [81], exert anti-inflammatory [85][86][87] and anti-convulsivant actions [88], increase food intake, body weight, and lean body mass (LBM) [81,89], play a role in the regulation of bone metabolism [90], display effects on gastric acid secretion and gastric emptying [91][92][93], and possess protective activity on the cardiovascular system both in vitro [94,95] and in vivo, both in animals [96][97][98] and humans [99,100]. GHS also prevent skeletal muscle damage in muscle wasting conditions associated to cancer cachexia [101][102][103] and/or cancer chemotherapy [8,9,36]. Indeed, because of positive effects on energy balance, ghrelin or GHS are considered a possible treatment option for all these cachexia-related conditions.…”

“…Body weight and food intake of these animals are significantly reduced following cisplatin administration. In particular, the final body weights of cisplatin-treated animals show a reduction of about 30% [5][6][7][8][9]. These adverse effects appear already from the first day of cisplatin administration and remain evident for the duration of the experimental protocol [8,9].…”

“…Furthermore, it is also well known that molecular mechanisms controlling muscle wasting in chemotherapy and cancer share common features with pathophysiology of other relevant muscle neurodegenerative such as muscular dystrophies [3,4]. The animal model commonly used to study the derangements specifically associated with chemotherapy and for testing new therapies for cachexia is the rat or mouse intraperitoneally treated with cisplatin (1-3 mg/kg) for 3-4 consecutive days to induce weight loss without over-toxicity [5][6][7][8][9]. Body weight and food intake of these animals are significantly reduced following cisplatin administration.…”

“…These adverse effects appear already from the first day of cisplatin administration and remain evident for the duration of the experimental protocol [8,9]. After cisplatin administration is halted, cisplatin-treated animals restart gaining weight and increase their food intake, but their body weight remains significantly lower than that of control animals [5,8,9].…”