Cardioprotective effects of AMPK activation in H1N1 influenza virus infection

Leumi, S.; McFadden, M.; Kumar, N.; Mattoo, S. S.; Roettger, J.; Speaks, S.; Liu, B.; Mohan, S.; Reznik, B.; Cable, J. M.; Denz, P. J.; Rajaram, M. V. S.; Forero, A.; Yount, J. S.

doi:10.1101/2025.08.28.672931

bioRxiv · 10.1101/2025.08.28.672931

Cardioprotective effects of AMPK activation in H1N1 influenza virus infection

Leumi, S.·McFadden, M.·Kumar, N.·Mattoo, S. S.·Roettger, J.·Speaks, S.·Liu, B.·Mohan, S.·Reznik, B.·Cable, J. M.·Denz, P. J.·Rajaram, M. V. S.·Forero, A.·Yount, J. S.

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Abstract

Cardiac complications are among the most common and severe extrapulmonary manifestations of influenza virus infection, yet they are rarely recapitulated in mouse models without immunodeficiency. We found that influenza virus A/California/04/2009 (H1N1) carrying a mouse-adaptive amino acid substitution in the PB2 protein (E158A) disseminates to the heart in WT C57BL/6 mice, where it induces inflammation, electrical dysfunction, and fibrotic remodeling. Influenza virus-infected heart tissue was significantly altered in mitochondrial metabolism, extracellular matrix, circadian rhythm, and immunity pathways. Particularly striking was activation of gene expression downstream of the mitochondrial biogenesis-promoting AMPK/PGC-1 axis, which occurred late in infection but failed to reverse the repression of mitochondria-associated genes, suggesting an insufficient or delayed compensatory response. Accordingly, we administered AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) early in infection and observed restoration of mitochondria-associated gene levels, amelioration of cardiac electrical dysfunction and fibrosis, and improvement in survival without overt effects on lung function. Overall, the advent of an immunocompetent model for severe influenza-associated cardiac dysfunction revealed activation of AMPK signaling as a host-targeted metabolic intervention for mitigating virus-induced heart pathologies

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Leumi, S., McFadden, M., Kumar, N., Mattoo, S. S., Roettger, J., Speaks, S., Liu, B., Mohan, S., Reznik, B., Cable, J. M., Denz, P. J., Rajaram, M. V. S., Forero, A., Yount, J. S.. 2025-08-28. Cardioprotective effects of AMPK activation in H1N1 influenza virus infection. https://doi.org/10.1101/2025.08.28.672931

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