| Naslov: | Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca2+ cycling |
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| Avtorji: | ID Ljubojevic-Holzer, Senka (Avtor)
ID Kraler, Simon (Avtor)
ID Djalinac, Nataša (Avtor)
ID Abdellatif, Mahmoud (Avtor)
ID Voglhuber, Julia (Avtor)
ID Schipke, Julia (Avtor)
ID Schmidt, Marlene (Avtor)
ID Kling, Katharina-Maria (Avtor)
ID Franke, Greta Therese (Avtor)
ID Herbst, Viktoria (Avtor)
ID Sedej, Simon (Avtor), et al. |
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| Datoteke: |  Ljubojevic-Holz-2022-Loss_of_autophagy_protein.pdf (1,87 MB)
MD5: 3080780ED9DC2DF458D27CD92C6E64BE
 https://doi.org/10.1093/cvr/cvab112
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| Jezik: | Angleški jezik |
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| Vrsta gradiva: | Znanstveno delo |
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| Tipologija: | 1.01 - Izvirni znanstveni članek |
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| Organizacija: | MF - Medicinska fakulteta
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| Opis: | 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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| Ključne besede: | autophagy, beta-adrenergic signalling, calcium, cardiomyocytes, mitochondria |
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| Status publikacije: | Objavljeno |
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| Verzija publikacije: | Objavljena publikacija |
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| Poslano v recenzijo: | 23.01.2021 |
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| Datum sprejetja članka: | 19.03.2021 |
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| Datum objave: | 22.03.2021 |
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| Založnik: | British Medical Association, Oxford University Press |
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| Leto izida: | 2022 |
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| Št. strani: | Str. 1492-1505 |
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| Številčenje: | Letn. 118, Št. 6 |
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| PID: | 20.500.12556/DKUM-90833  |
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| UDK: | 616.12 |
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| COBISS.SI-ID: | 159499267 |
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| DOI: | 10.1093/cvr/cvab112 |
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| ISSN pri članku: | 1755-3245 |
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| Datum objave v DKUM: | 26.09.2024 |
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| Število ogledov: | 176 |
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| Število prenosov: | 12 |
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| Metapodatki: |    |
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| Področja: | Ostalo
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