Key result
Loss of Atg5-dependent autophagy reduced mitochondrial abundance and disrupted subcellular Ca2+ cycling upon increased workload, leading to compromised cardiac reserve.
Why the study?
While aberrant Ca2+ handling promotes myocardial remodelling and contractile dysfunction, the role of autophagy in maintaining Ca2+ homeostasis remains elusive.
Does Atg5 deficiency-mediated autophagy impairment reduce cardiac reserve capacity and disrupt Ca2+ cycling in ventricular cardiomyocytes?
Does Atg5 deficiency-mediated autophagy impairment reduce cardiac reserve capacity and disrupt Ca2+ cycling in ventricular cardiomyocytes?
Loss of Atg5-dependent autophagy impairs cardiac reserve capacity by reducing mitochondrial abundance and disrupting subcellular Ca2+ cycling under increased workload.
Does not support clinical autophagy targeting; hypothesis-generating for Atg5 in human cardiac reserve and Ca2+ handling.
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.
No takes yet. Share an insight, caveat, or question.
Ljubojević-Holzer et al. (2021) studied Cardiac hypertrophy and failure. Atg5 deficiency vs. Normal Atg5 function was evaluated on Cardiac reserve capacity, subcellular Ca2+ handling, and mitochondrial abundance. Loss of Atg5-dependent autophagy reduced mitochondrial abundance and disrupted subcellular Ca2+ cycling upon increased workload, leading to compromised cardiac reserve.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: