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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Ljubojević-Holzer, S; Kraler, S; Djalinac, N; Abdellatif, M; Voglhuber, J; Schipke, J; Schmidt, M; Kling, KM; Franke, GT; Herbst, V; Zirlik, A; von, Lewinski, D; Scherr, D; Rainer, PP; Kohlhaas, M; Nickel, A; Mühlfeld, C; Maack, C; Sedej, S.
Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca2+ cycling.
Cardiovasc Res. 2022; 118(6):1492-1505 Doi: 10.1093/cvr/cvab112 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Holzer Senka
Kraler Simon
Sedej Simon
Co-Autor*innen der Med Uni Graz
Abdellatif Mahmoud
Dalinac Natasa
Rainer Peter
Scherr Daniel
Trummer-Herbst Viktoria
Voglhuber Julia
von Lewinski Dirk
Zirlik Andreas

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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.
Find related publications in this database (using NLM MeSH Indexing)
Adrenergic Agents - metabolism
Animals - administration & dosage
Autophagy - administration & dosage
Autophagy-Related Protein 5 - genetics, metabolism
Calcium - metabolism
Humans - administration & dosage
Mice - administration & dosage
Mice, Knockout - administration & dosage
Mitochondria - metabolism
Myocytes, Cardiac - metabolism

Find related publications in this database (Keywords)
Beta-adrenergic signalling
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