Ghrelin and Its Analogues, BIM-28131 and BIM-28125, Improve Body Weight and Regulate the Expression of MuRF-1 and MAFbx in a Rat Heart Failure Model

Cardiac cachexia is a serious complication of chronic heart failure with a prevalence of 10-16% and poor prognosis. There are no current therapy options for cardiac cachexia. Ghrelin is the natural ligand for the GHS-1a-receptor and a potential target for conditions associated with cachexia. Ghrelin has been shown to increase weight in several species. The GHS-1a-receptor is not only found in the brain, but also in other tissues, including the myocardium. Human clinical trials with native ghrelin in cardiac cachexia demonstrated increases in appetite, weight and cardiac output. Methods: Human ghrelin or one of two analogues BIM-28125 and BIM-28131 (also known as RM-131) were tested at 50 nmole/kg/d and 500 nmole/kg/d versus placebo in a ratmodel of heart failure (myocardial infarction). Animals (SD-rats, approx. 225 g at surgery) received diuretics from day 14 and compounds from day 28 for 4 weeks using osmotic pumps. Weight was monitored and body composition analysed (NMR-scanning). Cardiac function was assessed by echocardiography and hemodynamics. Results: Animals with MI gained less weight compared to sham rats until start of the therapy (311 g vs 324 g, p = 0.0129). Animals treated with BIM-28131 at 50 nmole/kg/d or all compounds at 500 nmole/kg/d displayed stronger weight gain compared to placebo and sham (all p < 0.001). Before treatment, body composition was similar in all groups (average: 36 g fat, 248 g lean). Placebo-treated rats gained no fat, but only lean mass. The active compounds induced both fat and lean mass gain, but to a different extent. The fat-to-muscle-ratio of tissue gain was 0.9 +/- 0.07 for BIM-28131 at 50 nmole/kg/d, whereas at 500 nmole/kg/d it was 0.76 +/- 0.07 for BIM-28131, 0.68 +/- 0.12 for BIM-28125, and 0.48 +/- 0.05 for ghrelin. MuRF-1 and MAFbx were differentially regulated by treatment. Conclusion: Ghrelin is a very promising treatment option for cardiac cachexia, with the analogue BIM-28131 (RM-131) being the most effective compound.