Browsing by Subject "Nutrient sensing"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    A remarkable adaptive paradigm of heart performance and protection emerges in response to marked cardiac-specific overexpression of ADCY8
    (eLife Sciences, 2022-12-14) Tarasov, Kirill V.; Chakir, Khalid; Riordon, Daniel R.; Lyashkov, Alexey E.; Ahmet, Ismayil; Perino, Maria Grazia; Silvester, Allwin Jennifa; Zhang, Jing; Wang, Mingyi; Lukyanenko, Yevgeniya O.; Qu, Jia-Hua; Barrera, Miguel Calvo-Rubio; Juhaszova, Magdalena; Tarasova, Yelena S.; Ziman, Bruce; Telljohann, Richard; Kumar, Vikas; Ranek, Mark; Lammons, John; Bychkov, Rostislav; de Cabo, Rafael; Jun, Seungho; Keceli, Gizem; Gupta, Ashish; Yang, Dongmei; Aon, Miguel A.; Adamo, Luigi; Morrell, Christopher H.; Otu, Walter; Carroll, Cameron; Chambers, Shane; Paolocci, Nazareno; Huynh, Thanh; Pacak, Karel; Weiss, Robert; Field, Loren; Sollott, Steven J.; Lakatta, Edward G.; Medicine, School of Medicine
    Adult (3 month) mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TGAC8) adapt to an increased cAMP-induced cardiac workload (~30% increases in heart rate, ejection fraction and cardiac output) for up to a year without signs of heart failure or excessive mortality. Here, we show classical cardiac hypertrophy markers were absent in TGAC8, and that total left ventricular (LV) mass was not increased: a reduced LV cavity volume in TGAC8 was encased by thicker LV walls harboring an increased number of small cardiac myocytes, and a network of small interstitial proliferative non-cardiac myocytes compared to wild type (WT) littermates; Protein synthesis, proteosome activity, and autophagy were enhanced in TGAC8 vs WT, and Nrf-2, Hsp90α, and ACC2 protein levels were increased. Despite increased energy demands in vivo LV ATP and phosphocreatine levels in TGAC8 did not differ from WT. Unbiased omics analyses identified more than 2,000 transcripts and proteins, comprising a broad array of biological processes across multiple cellular compartments, which differed by genotype; compared to WT, in TGAC8 there was a shift from fatty acid oxidation to aerobic glycolysis in the context of increased utilization of the pentose phosphate shunt and nucleotide synthesis. Thus, marked overexpression of AC8 engages complex, coordinate adaptation "circuity" that has evolved in mammalian cells to defend against stress that threatens health or life (elements of which have already been shown to be central to cardiac ischemic pre-conditioning and exercise endurance cardiac conditioning) that may be of biological significance to allow for proper healing in disease states such as infarction or failure of the heart.
  • Thumbnail Image
    Item
    Physiologic Responses to Dietary Sulfur Amino Acid Restriction in Mice Are Influenced by Atf4 Status and Biological Sex
    (Oxford University Press, 2021-04-08) Jonsson, William O.; Margolies, Nicholas S.; Mirek, Emily T.; Zhang, Qian; Linden, Melissa A.; Hill, Cristal M.; Link, Christopher; Bithi, Nazmin; Zalma, Brian; Levy, Jordan L.; Pettit, Ashley P.; Miller, Joshua W.; Hine, Christopher; Morrison, Christopher D.; Gettys, Thomas W.; Miller, Benjamin F.; Hamilton, Karyn L.; Wek, Ronald C.; Anthony, Tracy G.; Biochemistry and Molecular Biology, School of Medicine
    Background: Dietary sulfur amino acid restriction (SAAR) improves body composition and metabolic health across several model organisms in part through induction of the integrated stress response (ISR). Objective: We investigate the hypothesis that activating transcription factor 4 (ATF4) acts as a converging point in the ISR during SAAR. Methods: Using liver-specific or global gene ablation strategies, in both female and male mice, we address the role of ATF4 during dietary SAAR. Results: We show that ATF4 is dispensable in the chronic induction of the hepatokine fibroblast growth factor 21 while being essential for the sustained production of endogenous hydrogen sulfide. We also affirm that biological sex, independent of ATF4 status, is a determinant of the response to dietary SAAR. Conclusions: Our results suggest that auxiliary components of the ISR, which are independent of ATF4, are critical for SAAR-mediated improvements in metabolic health in mice.