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Exploring the Role of NAD+ Homeostasis in Cardiac Hypertrophy and Functional Abnormalities in a Mouse Model of Friedreich's Ataxia / Caroline Elisabeth Perry.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Perry, Caroline Elisabeth, author.
- Language:
- English
- Subjects (All):
- Biology.
- Medicine.
- Molecular biology.
- Biomechanics.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Local Subjects:
- Biology.
- Medicine.
- Molecular biology.
- Biomechanics.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Physical Description:
- 1 online resource (146 pages)
- Contained In:
- Dissertations Abstracts International 85-12B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- Language Note:
- English
- Summary:
- Nearly half of all adults in the United States are currently living with some form of cardiovascular disease. In many cases this progresses to heart failure, for which there is no cure. In human heart failure, a decline in nicotinamide adenine dinucleotide (NAD+) has been observed in heart tissue. In multiple rodent models of heart failure, administration of NAD+ precursors has been shown to improve cardiac function. FRDA is a progressive disorder caused by insufficient expression of frataxin, which plays a critical role in assembly of iron-sulfur clusters in mitochondria. Many individuals with FRDA ultimately develop heart failure. We hypothesized that loss of NAD+ within mitochondria might contribute to cardiomyopathy in these individuals. To test this hypothesis, as well as the broader role of NAD+ in a relevant model of FRDA, we studied mice with systemic knockdown of frataxin (shFxn), which display motor deficits and early mortality with cardiac hypertrophy. We found that hearts in these mice did not "fail" per se but become hyperdynamic with small chamber size. Hearts from shFxn mice had lower tissue NAD+, consistent with other models of heart failure, but maintained the mitochondrial NAD+ level despite mitochondrial dysfunction. Administering nicotinamide mononucleotide or riboside increased survival and modestly improved cardiac hypertrophy. Mechanistically, most of the transcriptional and metabolic changes induced by frataxin knockdown were insensitive to treatment, but total glutathione levels increased suggesting improved antioxidant capacity. To test whether mitochondrial NAD+ decline could result in hypertrophy or heart failure, we studied mice with reduced expression of the mitochondrial NAD+ carrier SLC25A51. We found that aging mouse hearts are resilient to mitochondrial NAD+ decline. Altogether, we demonstrate that a partial decline in mitochondrial NAD+ does not contribute to the pathology in this model of FRDA, and is not sufficient to cause heart failure. Our findings indicate that in the context of FRDA, which exhibits NAD+ depletion and cardiac hypertrophy, NAD+ precursors are modestly cardioprotective and prolong survival, likely independently from mitochondrial NAD+.
- Notes:
- Source: Dissertations Abstracts International, Volume: 85-12, Section: B.
- Advisors: Baur, Joseph A.; Committee members: Simon, M. Celeste; Wilson, Robert B.; Lynch, David R.; Titchenell, Paul M.; Arany, Zoltan P.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2024.
- Local Notes:
- School code: 0175
- ISBN:
- 9798382835372
- Access Restriction:
- Restricted for use by site license.
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