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• W4385838075 abstract "ABSTRACT BACKGROUND Dysregulated proteostasis leading to accumulation of misfolded proteins, electron-dense aggregates (lipofuscin, LF), desmin preamyloid oligomers (PAOs), and proteotoxic stress is a hallmark of aging. We investigated how efficiently proteostatic adaptations to chronic cardiac cyclic adenosine monophosphate (cAMP)-dependent stress change with aging, in mice harboring a marked, cardiac-specific over-expression of adenylyl cyclase VIII (TG AC8 ). METHODS Protein quality control (PQC) mechanisms (ubiquitin proteasome system (UPS) and autophagy), including mitophagy, in TG AC8 and wild time littermates (WT) were evaluated in left ventricle (LV) at 3-4 months and at 17-21 months of age. Autophagy flux was evaluated in response to the lysosomotropic agent chloroquine (CQ), and protein synthesis was assessed according to the SUnSET puromycin method. RESULTS At 3-4 months of age, established autophagy markers such as the microtubule-associated protein 1 light chain 3 (LC3), p62, and their phospho-forms in TG AC8 LV were modulated to result in a more efficient autophagy. Flux was increased compared to WT. Lysosome performance (cathepsin L1 activity) in TG AC8 was also significantly increased, confirming higher cargo degradation and a more efficient proteostasis at 3-4 months. In advanced age, however, insufficiency of PQC mechanisms, manifested by a reduced proteasome activity, and an unbalanced autophagic flux, accelerated for markers such as LC3A and p62 within the context of a slower overall flux, led to an increase in the accumulation of aggresomes (increased ratio of insoluble/soluble protein fractions). In addition, although at 3-4 months canonical mitophagy signaling was increased (receptors PARKIN, p62-S403 and p62-S349 were upregulated) and non-canonical mitophagy signaling not engaged (receptor FKBP8 was decreased), both were upregulated at 18-21 months of age in TG AC8 , as protein levels of all receptors remained elevated. In old TG AC8 , the markedly impaired mitophagy, accompanied by the accumulation of lipofuscin (LF) bodies of aberrant sizes and brownish-to black pigment, increased concentration of cardiac preamyloid oligomers (PAOs) and elevated levels of cleaved desmin, tagged for ubiquitination, were characteristics of the age-effect compared to young TG AC8 . The rate of protein synthesis and levels of soluble aggregates were decreased, consequences of “normal” aging. CONCLUSIONS Proteostasis maintains cardiac health in TG AC8 in youth (3-4 months), but a long-term exposure to chronic pathophysiologic states that increase cardiac ubiquitination and stress, in response to sustained activation of the AC/cAMP/PKA/Ca 2+ axis, results in severely dysregulated proteostasis in TG AC8 vs WT, and is associated with proteostatic insufficiency, and accelerated cardiac aging. GRAPHIC ABSTRACT A graphic abstract is available for this article. GRAPHIC ABSTRACT/DIAGRAM Table. Proteostasis in young and aged TG AC8 in the context of cardiac stress in response to cardiac-specific constitutive stimulation of the AC/cAMP/PKA/Ca 2+ axis by α-MHC-driven AC8 overexpression." @default.
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• W4385838075 date "2023-08-14" @default.
• W4385838075 modified "2023-10-14" @default.
• W4385838075 title "Protective concentric cardiac proteostasis adaptations to chronic cAMP-stress at young ages wanes in advanced age leading to accelerated cardiac aging" @default.
• W4385838075 cites W1963688739 @default.
• W4385838075 cites W1966387364 @default.
• W4385838075 cites W1980062352 @default.
• W4385838075 cites W1980650534 @default.
• W4385838075 cites W1982359145 @default.
• W4385838075 cites W1987034100 @default.
• W4385838075 cites W1988146888 @default.
• W4385838075 cites W1990138203 @default.
• W4385838075 cites W1992091494 @default.
• W4385838075 cites W1992532731 @default.
• W4385838075 cites W1994823455 @default.
• W4385838075 cites W2001220477 @default.
• W4385838075 cites W2007006796 @default.
• W4385838075 cites W2007599736 @default.
• W4385838075 cites W2007695276 @default.
• W4385838075 cites W2009125409 @default.
• W4385838075 cites W2014918593 @default.
• W4385838075 cites W2016995597 @default.
• W4385838075 cites W2022675211 @default.
• W4385838075 cites W2023598683 @default.
• W4385838075 cites W2028587126 @default.
• W4385838075 cites W2029013337 @default.
• W4385838075 cites W2047577462 @default.
• W4385838075 cites W2069866232 @default.
• W4385838075 cites W2073941831 @default.
• W4385838075 cites W2078004915 @default.
• W4385838075 cites W2080693065 @default.
• W4385838075 cites W2084034472 @default.
• W4385838075 cites W2111511937 @default.
• W4385838075 cites W2113175552 @default.
• W4385838075 cites W2114806766 @default.
• W4385838075 cites W2116504706 @default.
• W4385838075 cites W2121963977 @default.
• W4385838075 cites W2141625411 @default.
• W4385838075 cites W2141654757 @default.
• W4385838075 cites W2145419893 @default.
• W4385838075 cites W2146124002 @default.
• W4385838075 cites W2149761960 @default.
• W4385838075 cites W2155015733 @default.
• W4385838075 cites W2156363822 @default.
• W4385838075 cites W2160411684 @default.
• W4385838075 cites W2161199002 @default.
• W4385838075 cites W2162871402 @default.
• W4385838075 cites W2164472512 @default.
• W4385838075 cites W2166068071 @default.
• W4385838075 cites W2166155880 @default.
• W4385838075 cites W2167192779 @default.
• W4385838075 cites W2168365305 @default.
• W4385838075 cites W2177646965 @default.
• W4385838075 cites W2240518777 @default.
• W4385838075 cites W2300762239 @default.
• W4385838075 cites W2318536322 @default.
• W4385838075 cites W2580787355 @default.
• W4385838075 cites W2604819250 @default.
• W4385838075 cites W2767687282 @default.
• W4385838075 cites W2773258360 @default.
• W4385838075 cites W2789289361 @default.
• W4385838075 cites W2796660004 @default.
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• W4385838075 cites W2890738628 @default.
• W4385838075 cites W2895013649 @default.
• W4385838075 cites W2904330826 @default.
• W4385838075 cites W2906801617 @default.
• W4385838075 cites W2950126964 @default.
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• W4385838075 doi "https://doi.org/10.1101/2023.08.13.553128" @default.
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