Journal article
Age-dependent decline in cardiac function in guanidinoacetate-N-methyltransferase knockout mice
- Abstract:
- Aim:Guanidinoacetate N-methyltransferase (GAMT) is the second essential enzyme in creatine (Cr) biosynthesis. Short-term Cr deficiency is metabolically well tolerated as GAMT-/- mice exhibit normal exercise capacity and response to ischemic heart failure. However, we hypothesized long-term consequences of Cr deficiency and/or accumulation of the Cr precursor guanidinoacetate (GA). Methods:Cardiac function and metabolic profile were studied in GAMT-/- mice >1 year. Results:In vivo LV catheterization revealed lower heart rate and developed pressure in aging GAMT-/- but normal lung weight and survival versus age-matched controls. Electron microscopy indicated reduced mitochondrial volume density in GAMT-/- hearts (P < 0.001), corroborated by lower mtDNA copy number (P < 0.004), and citrate synthase activity (P < 0.05), however, without impaired mitochondrial respiration. Furthermore, myocardial energy stores and key ATP homeostatic enzymes were barely altered, while pathology was unrelated to oxidative stress since superoxide production and protein carbonylation were unaffected. Gene expression of PGC-1α was 2.5-fold higher in GAMT-/- hearts while downstream genes were not activated, implicating a dysfunction in mitochondrial biogenesis signaling. This was normalized by 10 days of dietary Cr supplementation, as were all in vivo functional parameters, however, it was not possible to differentiate whether relief from Cr deficiency or GA toxicity was causative. Conclusion:Long-term Cr deficiency in GAMT-/- mice reduces mitochondrial volume without affecting respiratory function, most likely due to impaired biogenesis. This is associated with hemodynamic changes without evidence of heart failure, which may represent an acceptable functional compromise in return for reduced energy demand in aging mice.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, 5.2MB, Terms of use)
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- Publisher copy:
- 10.3389/fphys.2019.01535
Authors
- Publisher:
- Frontiers Media
- Journal:
- Frontiers in physiology More from this journal
- Volume:
- 10
- Article number:
- 1535
- Publication date:
- 2019-01-01
- Acceptance date:
- 2019-12-05
- DOI:
- EISSN:
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1664-042X
- ISSN:
-
1664-042X
- Pmid:
-
32038270
- Language:
-
English
- Keywords:
- Pubs id:
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1084323
- Local pid:
-
pubs:1084323
- Deposit date:
-
2020-02-21
Terms of use
- Copyright holder:
- Aksentijević et al.
- Copyright date:
- 2020
- Rights statement:
- © 2020 Aksentijević, Zervou, Eykyn, McAndrew, Wallis, Schneider, Neubauer and Lygate. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
- Licence:
- CC Attribution (CC BY)
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