@article{LjubojevićHolzerKralerDjalinacetal.2022,
  author    = {Ljubojević-Holzer, Senka and Kraler, Simon and Djalinac, Nataša and Abdellatif, Mahmoud and Voglhuber, Julia and Schipke, Julia and Schmidt, Marlene and Kling, Katharina-Maria and Franke, Greta Therese and Herbst, Viktoria and Zirlik, Andreas and von Lewinski, Dirk and Scherr, Daniel and Rainer, Peter P and Kohlhaas, Michael and Nickel, Alexander and M{\"u}hlfeld, Christian and Maack, Christoph and Sedej, Simon},
  title     = {Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca2+ cycling},
  series = {Cardiovascular Research},
  volume    = {118},
  journal   = {Cardiovascular Research},
  doi       = {10.1093/cvr/cvab112},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369345},
  pages     = {1492-1505},
  year      = {2022},
  abstract  = {Aims Autophagy protects against the development of cardiac hypertrophy and failure. While aberrant Ca2+ handling promotes myocardial remodelling and contributes to contractile dysfunction, the role of autophagy in maintaining Ca2+ homeostasis remains elusive. Here, we examined whether Atg5 deficiency-mediated autophagy promotes early changes in subcellular Ca2+ handling in ventricular cardiomyocytes, and whether those alterations associate with compromised cardiac reserve capacity, which commonly precedes the onset of heart failure. Methods and results RT-qPCR and immunoblotting demonstrated reduced Atg5 gene and protein expression and decreased abundancy of autophagy markers in hypertrophied and failing human hearts. The function of ATG5 was examined using cardiomyocyte-specific Atg5-knockout mice (Atg5-/-). Before manifesting cardiac dysfunction, Atg5-/- mice showed compromised cardiac reserve in response to β-adrenergic stimulation. Consequently, effort intolerance and maximal oxygen consumption were reduced during treadmill-based exercise tolerance testing. Mechanistically, cellular imaging revealed that Atg5 deprivation did not alter spatial and functional organization of intracellular Ca2+ stores or affect Ca2+ cycling in response to slow pacing or upon acute isoprenaline administration. However, high-frequency stimulation exposed stunted amplitude of Ca2+ transients, augmented nucleoplasmic Ca2+ load, and increased CaMKII activity, especially in the nuclear region of hypertrophied Atg5-/- cardiomyocytes. These changes in Ca2+ cycling were recapitulated in hypertrophied human cardiomyocytes. Finally, ultrastructural analysis revealed accumulation of mitochondria with reduced volume and size distribution, meanwhile functional measurements showed impaired redox balance in Atg5-/- cardiomyocytes, implying energetic unsustainability due to overcompensation of single mitochondria, particularly under increased workload. Conclusion Loss of cardiac Atg5-dependent autophagy reduces mitochondrial abundance and causes subtle alterations in subcellular Ca2+ cycling upon increased workload in mice. Autophagy-related impairment of Ca2+ handling is progressively worsened by β-adrenergic signalling in ventricular cardiomyocytes, thereby leading to energetic exhaustion and compromised cardiac reserve.},
  language  = {en}
}