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Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy

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Science  04 Aug 2017:
Vol. 357, Issue 6350, pp. 507-511
DOI: 10.1126/science.aah5582

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  • RE: Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy
    • Gabriele G. Schiattarella, Researcher, Cardiologist, Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas
    • Other Contributors:
      • Joseph A. Hill, Chief of Cardiology, Departments of Internal Medicine (Cardiology) and Molecular Biology, University of Texas Southwestern Medical Center, Dallas

    We read with interest the article by Myers and coworkers (1) regarding the antidiabetogenic effects of a novel 5′-adenosine monophosphate-activated protein kinase (AMPK) activator called MK-8722. In both rodents and non-human primate models of diabetes, MK-8722 exhibited beneficial effects on glucose homeostasis which potentially identify this drug as a significant advance in the pharmacological treatment of diabetes. However, MK-8722 administration elicited cardiac hypertrophy. Although the authors attempted to deemphasize this issue, significant concerns exist.
    Based on the nature of stress imposed on the cardiac ventricles, the resulting hypertrophic growth response can be classified as pathological or physiological; whereas the former is invariably associated with increased risk of heart failure and death, the latter is not. Besides their triggers and outcomes, pathological and physiological cardiac hypertrophy differ in the signaling pathways involved (2). Although AMPK has been more frequently associated with physiological cardiomyocyte growth (3), genetic interventions that resemble the chronic activation of AMPK induced by MK-8722 provoke cardiac hypertrophy which leads, over time, to ventricular dilation and heart failure (4, 5). Evidence in this report that crude parameters of contractile function did not change during a short period of observation (1 month) risk underestimating the potential detrimental effects of this compound on cardiac function, especia...

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    Competing Interests: None declared.

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