Cookies help us deliver our services. By using our services, you agree to our use of cookies. More information

Ljubojevic-Holzer 2021 Cardiovasc Res

From Bioblast
Publications in the MiPMap
Ljubojevic-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, Muehlfeld C, Maack C, Sedej S (2021) Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca2+ cycling.

» Cardiovasc Res 118:1492-505. PMID: 33752242 Open Access

Ljubojevic-Holzer Senka, Kraler Simon, Djalinac Natasa, Abdellatif Mahmoud, Voglhuber Julia, Schipke Julia, Schmidt Marlene, Kling Katharina-Maria, Franke Greta Therese, Herbst Viktoria, Zirlik Andreas, von Lewinski Dirk, Scherr Daniel, Rainer Peter P, Kohlhaas Michael, Nickel Alexander, Muehlfeld Christian, Maack Christoph, Sedej Simon (2021) Cardiovasc Res

Abstract: 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.

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.

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. Keywords: Autophagy, Beta-adrenergic signalling, Calcium, Cardiomyocytes, Mitochondria Bioblast editor: Reiswig R O2k-Network Lab: DE Wuerzburg Maack C

Labels: MiParea: Respiration, Genetic knockout;overexpression  Pathology: Cardiovascular 

Organism: Mouse  Tissue;cell: Heart  Preparation: Isolated mitochondria 

Coupling state: LEAK, OXPHOS, ET  Pathway: F, N  HRR: Oxygraph-2k 

2021-08, TMRM