Clenbuterol Induces Cardiac Myocyte Hypertrophy via Paracrine Signalling and Fibroblast-derived IGF-1

Abstract

The β(2)-selective adrenoreceptor agonist clenbuterol promotes both skeletal and cardiac muscle hypertrophy and is undergoing clinical trials in the treatment of muscle wasting and heart failure. We have previously demonstrated that clenbuterol induces a mild physiological ventricular hypertrophy in vivo with normal contractile function and without induction of α-skeletal muscle actin (αSkA), a marker of pathological hypertrophy. The mechanisms of this response remain poorly defined. In this study, we examine the direct action of clenbuterol on cardiocyte cultures in vitro. Clenbuterol treatment resulted in increased cell size of cardiac myocytes with increased protein accumulation and myofibrillar organisation characteristic of hypertrophic growth. Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) revealed elevated mRNA expression of ANP and brain natriuretic peptide (BNP) but without change in αSkA, consistent with physiological hypertrophic growth. Clenbuterol-treated cultures also showed elevated insulin-like growth factor I (IGF-1) mRNA and activation of the protein kinase Akt. Addition of either IGF-1 receptor-blocking antibodies or LY294002 in order to inhibit phosphatidylinositol 3-kinase, a downstream effector of the IGF-1 receptor, inhibited the hypertrophic response indicating that IGF-1 signalling is required. IGF-1 expression localised primarily to the minor population of cardiac fibroblasts present in the cardiocyte cultures. Together these data show that clenbuterol acts to induce mild cardiac hypertrophy in cardiac myocytes via paracrine signalling involving fibroblast-derived IGF-1.

Reverse Remodelling and Recovery from Heart Failure Are Associated with Complex Patterns of Gene Expression

“…Given that fibrosis is an obstacle to recovery, it would follow that high IGF1/pro-fibrotic patients benefit most from combined LVAD support and pharmacological management, whilst the low IGF1/pro-fibrotic patients are most likely to recover spontaneously. In the latter group, potential stimuli of IGF1 up-regulation include mechanical unloading as seen in the rat model of heterotopic transplantation [41] and clenbuterol induction of IGF1 in cardiac fibroblasts [42]. Further work is required to establish how the observed patterns of pro-fibrotic gene expression relate to histological measurements of fibrosis and to determine whether IGF1 is coordinating or tracking the fibrotic response during myocardial recovery.…”

Myocardial Self-Repair and Congenital Heart Disease

“…Testing the effects of clenbuterol on mechanical unloading, they were able to show that it improves LV function. Bhavsar demonstrated that clenbuterol positively affects cardiac physiology through myocyte hypertrophy, concluding that the effect was mediated by a paracrine action of fibroblast-derived IGF-1 (Bhavsar et al, 2010). At the present time, we can find no reports of an effect of clenbuterol on CPC recruitment/activation.…”

Myocardial Recovery Following Left Ventricular Assist Device Therapy

“…Findings of positive correlation between IGF-1 levels and MMPs 11, 14, TIMPs 1 and 2 as well as stem cell recruitment factor SDF-1 expression, advocate modulation of the ECM and cellular regeneration to be important (Barton et al 2005;Hall et al 2004). Clenbuterol treatment of cultured cardiomyocytes has been shown to increase fibroblastderived IGF-1, causing myocyte hypertrophy via paracrine signalling (Bhavsar et al 2010;Hall et al 2004). This suggests that IGF-mediated prevention of myocardial atrophy may also be involved in promoting functional recovery.…”

“…In addition, a clear cardioprotective inhibitory G protein dependent anti-apoptotic effect of acute clenbuterol administration has been recently shown during ischaemia reperfusion (Zhang et al 2010). Clenbuterol modulation of IGF-1 dependent regenerative and hypertrophic pathways, as well as ECM effects may also be responsible for promoting functional recovery (Barton et al 2005;Bhavsar et al 2010;Hall et al 2004). …”