Effect of ghrelin and its analogues, BIM-28131 and BIM-28125, on the expression of myostatin in a rat heart failure model

BACKGROUND: In chronic heart failure (CHF), cachexia is a hallmark of the terminal stage of this disease and is associated with a severely reduced quality of life and poor prognosis. Therapeutic options are currently not available. Ghrelin and its analogues BIM-28125 and BIM-28131 (now known as RM-131) have been shown to increase weight in a rat model of CHF. It has been further demonstrated that the expression of myostatin, a negative regulator of skeletal muscle mass, is increased in CHF. The aim of the study was to investigate the influence of ghrelin or its analogues on myostatin in CHF. METHODS: In an animal model of CHF, Sprague–Dawley rats received either ghrelin or two ghrelin analogues BIM-28125 and BIM-28131 in two different concentrations (50 and 500 nmol/kg/day) compared to placebo. The compounds were delivered using osmotic mini pumps. The expression of myostatin was analyzed in skeletal muscle by RT-PCR and Western blot, and muscle mass of gastrocnemius muscle was measured. The plasma levels of tumor necrosis factor alpha (TNF-α) were measured. RESULTS: The relative weight of the gastrocnemius muscle of the sham-operated group was significantly increased compared to placebo-treated CHF rats. The application of ghrelin analogue BIM-28125 and BIM-28131 in their higher concentrations led to a significant reduction in myostatin mRNA expression in comparison to placebo. Myostatin protein expression was significantly reduced in both concentrations of ghrelin and BIM-28131 and in the lower concentration of BIM-28125. The increase of TNF-α plasma concentration in the CHF-animals could be abolished by all used substances. CONCLUSIONS: In an animal model of CHF, the expression of myostatin is significantly reduced in the skeletal muscle after application of ghrelin and most concentrations of its analogues BIM-28125 and BIM-28131 possibly due to anti-inflammatory effects.