Nicotinamide Riboside on Mitochondrial Function in Li-Fraumeni Syndrome
কীওয়ার্ডস
বিমূর্ত
বর্ণনা
We have previously reported that inherited mutations of TP53, which causes the premature cancer disorder Li-Fraumeni syndrome (LFS), can promote mitochondrial function both in patients and mouse models. In the course of our follow up studies, we encountered a LFS patient with a long-standing history of fatigue and muscle weakness of unclear etiology. Notably, we observed in vivo evidence of markedly decreased mitochondrial function in her leg skeletal muscle during exercise using noninvasive phosphorus-31 magnetic resonance spectroscopy (31P-MRS), a technique that has previously been used to study patients with primary mitochondrial disorders. The decrease in mitochondrial function was also confirmed by the patient s skin fibroblasts in vitro using standard biochemical measurements.
There is growing evidence that nicotinamide adenine dinucleotide (NAD+) homeostasis plays a significant role in maintaining the mitochondria through various mechanisms and that it is possible to improve mitochondrial function by dietary supplementation with the vitamin B3 analogue nicotinamide riboside (NR), an intermediate in the NAD+ salvage pathway. Remarkably, we observed that culturing the LFS patient s fibroblasts in medium containing NR rescued the severe deficit in mitochondrial respiration. While continuing our investigations into the molecular mechanism(s) underlying the mitochondrial dysfunction observed in this patient, the in vitro rescue of the respiratory deficiency by NR presents a unique opportunity to investigate whether it can also be observed in vivo using skeletal muscle 31P-MRS. We propose to explore the effect of NR, currently available as a dietary supplement, on in vivo mitochondrial function in this LFS patient.
তারিখ
সর্বশেষ যাচাই করা হয়েছে: | 11/25/2019 |
প্রথম জমা দেওয়া: | 12/26/2018 |
আনুমানিক তালিকাভুক্তি জমা দেওয়া হয়েছে: | 12/26/2018 |
প্রথম পোস্ট: | 12/27/2018 |
সর্বশেষ আপডেট জমা দেওয়া হয়েছে: | 05/06/2020 |
সর্বশেষ আপডেট পোস্ট: | 05/07/2020 |
আসল অধ্যয়ন শুরুর তারিখ: | 03/24/2019 |
আনুমানিক প্রাথমিক সমাপ্তির তারিখ: | 10/31/2019 |
আনুমানিক অধ্যয়ন সমাপ্তির তারিখ: | 10/31/2019 |
অবস্থা বা রোগ
হস্তক্ষেপ / চিকিত্সা
Dietary Supplement: Subjects receiving supplement
পর্যায়
বাহু গ্রুপ
বাহু | হস্তক্ষেপ / চিকিত্সা |
---|---|
Other: Subjects receiving supplement Subjects with Li-Fraumeni syndrome with TP53 mutations will receive NR | Dietary Supplement: Subjects receiving supplement Niacin is a form of vitamin B3 and has been used to treat hypercholesterolemia for many years. There is growing evidence that nicotinamide adenine dinucleotide (NAD+ can maintain mitochondria through various mechanisms and that it is possible to improve mitochondrial function by dietary supplementation with the vitamin B3 analogue nicotinamide riboside (NR), an intermediate in the NAD+ salvage pathway. We have observed that culturing the fibroblasts of a LFS patient with mitochondrial deficiency in medium containing NR rescues the defect in mitochondrial respiration. |
যোগ্যতার মানদণ্ড
বয়স অধ্যয়নের জন্য যোগ্য | 18 Years প্রতি 18 Years |
লিঙ্গ অধ্যয়নের জন্য যোগ্য | All |
স্বাস্থ্যকর স্বেচ্ছাসেবীদের গ্রহণ করে | হ্যাঁ |
নির্ণায়ক | - INCLUSION CRITERIA: - At least 18-years of age and able to give informed consent - Have delayed PCr recovery time constant >45 sec by 31P-MRS testing and a history of fatigue symptoms - Ability to undergo study procedures, including scheduled visits, blood draws and skeletal muscle exercise NMR spectroscopy - Have Li-Fraumeni syndrome and confirmed TP53 mutation by genetic testing - Committed to using reliable contraception which may include abstinence during study participation - Female participants of child-bearing ability and potential willing to commit to reliable contraception while participating in the study EXCLUSION CRITERIA: - Current systemic treatment for cancer - Unable to perform required study visits or procedures - MRI incompatible hardware - Pregnant or breastfeeding women - History of intolerance to NR precursor compounds, including niacin or nicotinamide |
ফলাফল
প্রাথমিক ফলাফল ব্যবস্থা
1. intra-subject comparison of baseline to 12 wk NR supplementation PCr recovery Tc measurements using the 31P-MRS skeletal muscle submaximal exercise. [12 weeks]
মাধ্যমিক ফলাফলের ব্যবস্থা
1. Examine whether NR supplementation affects the respiratory capacity of blood mononuclear cells, CPET, self-reported symptoms of fatigue. [7 months]