| Title: | Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca2+ cycling |
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| Authors: | ID Ljubojevic-Holzer, Senka (Author)
ID Kraler, Simon (Author)
ID Djalinac, Nataša (Author)
ID Abdellatif, Mahmoud (Author)
ID Voglhuber, Julia (Author)
ID Schipke, Julia (Author)
ID Schmidt, Marlene (Author)
ID Kling, Katharina-Maria (Author)
ID Franke, Greta Therese (Author)
ID Herbst, Viktoria (Author)
ID Sedej, Simon (Author), et al. |
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| Files: |  Ljubojevic-Holz-2022-Loss_of_autophagy_protein.pdf (1,87 MB)
MD5: 3080780ED9DC2DF458D27CD92C6E64BE
 https://doi.org/10.1093/cvr/cvab112
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| Language: | English |
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| Work type: | Scientific work |
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| Typology: | 1.01 - Original Scientific Article |
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| Organization: | MF - Faculty of Medicine
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| 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. |
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| Keywords: | autophagy, beta-adrenergic signalling, calcium, cardiomyocytes, mitochondria |
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| Publication status: | Published |
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| Publication version: | Version of Record |
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| Submitted for review: | 23.01.2021 |
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| Article acceptance date: | 19.03.2021 |
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| Publication date: | 22.03.2021 |
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| Publisher: | British Medical Association, Oxford University Press |
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| Year of publishing: | 2022 |
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| Number of pages: | Str. 1492-1505 |
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| Numbering: | Letn. 118, Št. 6 |
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| PID: | 20.500.12556/DKUM-90833  |
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| UDC: | 616.12 |
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| ISSN on article: | 1755-3245 |
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| COBISS.SI-ID: | 159499267 |
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| DOI: | 10.1093/cvr/cvab112 |
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| Publication date in DKUM: | 26.09.2024 |
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| Views: | 175 |
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| Downloads: | 12 |
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| Metadata: |    |
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| Categories: | Misc.
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