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

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Abstract

The β2-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.

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Acknowledgements

This work was supported by the British Heart Foundation and by the Magdi Yacoub Institute.

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Author notes

  1. Pankaj K. Bhavsar

    Present address: Airway Disease, National Heart and Lung Institute, Imperial College, London, UK

Authors and Affiliations

  1. Heart Science Centre, National Heart and Lung Institute, Imperial College, Harefield, Middlesex UB9 6JH, London, UK

    Pankaj K. Bhavsar, Nigel J. Brand, Leanne E. Felkin, Martin E. Cullen, Magdi H. Yacoub & Paul J. R. Barton

  2. Molecular Medicine, National Heart and Lung Institute, Imperial College, London, UK

    Pradeep K. Luther

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Correspondence to Paul J. R. Barton.

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Pankaj K. Bhavsar and Nigel J. Brand contributed equally to this paper.

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Bhavsar, P.K., Brand, N.J., Felkin, L.E. et al. Clenbuterol Induces Cardiac Myocyte Hypertrophy via Paracrine Signalling and Fibroblast-derived IGF-1. J. of Cardiovasc. Trans. Res. 3, 688–695 (2010). https://doi.org/10.1007/s12265-010-9199-1

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