Improving physical performance and cardiac function of Tafazzin deficient mice with nicotinamide riboside
Riekelt Houtkooper, PhD, Amsterdam University Medical Center
Barth Syndrome (BTHS; MIM 302060) is an X-linked recessive disorder, clinically characterized by cardio- and skeletal myopathy, neutropenia and growth abnormalities. BTHS is caused by mutations in the TAFAZZIN gene, encoding the TAFAZZIN protein that is required for the remodeling of cardiolipin (CL), a hallmark phospholipid of the mitochondrial inner membrane. Biochemically, BTHS patients suffer from a decrease in CL, an elevation of monolyso-CL (MLCL) levels, and a higher degree of saturation of the CL acyl chains.
There is no specific treatment for BTHS. In fact, therapies are focused on reducing and preventing complications. These include physical therapy to improve muscle tone, antibiotics to prevent or treat bacterial infections, and administration of medication to prevent heart failure. Therefore, exploring new therapeutics avenues to effectively treat BTHS is of outstanding relevance.
In this sense, we have recently demonstrated that administration of nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD+), effectively rescues exercise tolerance and mitochondrial respiration in a Drosophila Taz mutant. Building upon these results, we aim to validate this potential therapy in a Tafazzin knock-out mouse mutant. To do this, BTHS mice will be fed an NR-enriched diet for two months, during which locomotor activity, exercise capacity, and heart function will be monitored. At the end of the study, biochemical and molecular analyses will be performed, including (a) lipidomics to determine changes in CL and MLCL species; (b) metabolomics to test NAD+ levels, (c) RNAseq to establish widespread adaptations; (d) histopathology.
This project will shed light on whether NR supplementation is a valid therapy for BTHS in a mammalian organism, which is an essential step to take before translating this therapy to clinical trials.
