Researchers from Children’s Hospital of Philadelphia (CHOP) demonstrated how a member of the vitamin B3 family can help alleviate exercise intolerance in an animal model exhibiting a genetic variation that leads to impaired mitochondrial function.
The findings were recently published in the journal Molecular Metabolism.
Since mitochondria effectively serve as the “powerhouses” of our cells, impaired mitochondrial function can lead to fatigue and exercise intolerance, which result in severe limitations to the everyday life of patients. Building off a prior study, researchers focused on a specific gene called adenine nucleotide translocator isoform 1 (ANT1), which helps transport energy out of the mitochondria. Previous studies have shown that impaired function of ANT1 results in cardiomyopathy and exercise intolerance in both animals and humans.
In this study, the researchers used an animal model deficient in ANT1 to study how the absence of this gene impacts exercise physiology and mitochondrial function and how that function could potentially be restored.
“The goal of this study was to better understand the molecular mechanism that underlies the exercise intolerance brought upon by ANT1-deficiency,” said Patrick Schaefer, PhD, a postdoctoral fellow at the Center for Mitochondrial and Epigenomic Medicine at CHOP and first author of the study. “A more thorough understanding enables us to uncover possible targets to improve exercise capacity and ultimately the quality of life of patients with defects in ANT1 and other mitochondrial disorders.”
Using their ANT1-deficient model, the researchers showed that mitochondrial energy production within the skeletal muscle had the biggest impact on exercise capacity.Notably, the researchers observed reduced levels of nicotinamide adenine dinucleotide (NAD+), a coenzyme involved in hundreds of critical metabolic processes, which exacerbated the lack of energy in the skeletal muscle of the animal model.
When the ANT1-deficient model was treated with nicotinamide riboside, a member of the vitamin B3 family that is a precursor of NAD+, the researchers found increased NAD+ levels in skeletal muscle and liver tissue, which led to increased exercise capacity and mitochondrial respiration. This finding suggests that this vitamin, a freely available nutrient supplement, could improve exercise capacity and quality of life in mitochondrial disorders. However, two other animal models with different defects in their mitochondria did not positively respond to the nicotinamide riboside treatment, suggesting that the benefits are specifically related to ANT1 deficiency.
“This demonstrates the heterogeneity of mitochondrial disorders and emphasizes the need for personalized treatments,” said senior study author Douglas C. Wallace, PhD, director of the Center for Mitochondrial and Epigenomic Medicine at CHOP and the Michael and Charles Barnett Endowed Chair in Pediatric Mitochondrial Medicine and Metabolic Diseases.“Nicotinamide riboside is no panacea for mitochondrial disorders, but it might be a promising approach for some patients and suggests NAD+ supplementation should be considered in the context of mitochondrial disease therapeutics.”
This work was supported by the German Research Foundation grant SCHA2182/1-1 and National Institutes of Health grants Q2 NS021328, MH108592, OD010944 as well as U.S. Department of Defense grants W81XWH-16-1-0401 and W81XWH-21-1-0128.
Schaefer et al, “Nicotinamide Riboside alleviates exercise intolerance in ANT1-deficient mice.” Mol Metab. Published online 2022 August 6. DOI: 10.1016/j.molmet.2022.101560.
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Researchers from Children’s Hospital of Philadelphia (CHOP) demonstrated how a member of the vitamin B3 family can help alleviate exercise intolerance in an animal model exhibiting a genetic variation that leads to impaired mitochondrial function.
The findings were recently published in the journal Molecular Metabolism.
Since mitochondria effectively serve as the “powerhouses” of our cells, impaired mitochondrial function can lead to fatigue and exercise intolerance, which result in severe limitations to the everyday life of patients. Building off a prior study, researchers focused on a specific gene called adenine nucleotide translocator isoform 1 (ANT1), which helps transport energy out of the mitochondria. Previous studies have shown that impaired function of ANT1 results in cardiomyopathy and exercise intolerance in both animals and humans.
In this study, the researchers used an animal model deficient in ANT1 to study how the absence of this gene impacts exercise physiology and mitochondrial function and how that function could potentially be restored.
“The goal of this study was to better understand the molecular mechanism that underlies the exercise intolerance brought upon by ANT1-deficiency,” said Patrick Schaefer, PhD, a postdoctoral fellow at the Center for Mitochondrial and Epigenomic Medicine at CHOP and first author of the study. “A more thorough understanding enables us to uncover possible targets to improve exercise capacity and ultimately the quality of life of patients with defects in ANT1 and other mitochondrial disorders.”
Using their ANT1-deficient model, the researchers showed that mitochondrial energy production within the skeletal muscle had the biggest impact on exercise capacity.Notably, the researchers observed reduced levels of nicotinamide adenine dinucleotide (NAD+), a coenzyme involved in hundreds of critical metabolic processes, which exacerbated the lack of energy in the skeletal muscle of the animal model.
When the ANT1-deficient model was treated with nicotinamide riboside, a member of the vitamin B3 family that is a precursor of NAD+, the researchers found increased NAD+ levels in skeletal muscle and liver tissue, which led to increased exercise capacity and mitochondrial respiration. This finding suggests that this vitamin, a freely available nutrient supplement, could improve exercise capacity and quality of life in mitochondrial disorders. However, two other animal models with different defects in their mitochondria did not positively respond to the nicotinamide riboside treatment, suggesting that the benefits are specifically related to ANT1 deficiency.
“This demonstrates the heterogeneity of mitochondrial disorders and emphasizes the need for personalized treatments,” said senior study author Douglas C. Wallace, PhD, director of the Center for Mitochondrial and Epigenomic Medicine at CHOP and the Michael and Charles Barnett Endowed Chair in Pediatric Mitochondrial Medicine and Metabolic Diseases.“Nicotinamide riboside is no panacea for mitochondrial disorders, but it might be a promising approach for some patients and suggests NAD+ supplementation should be considered in the context of mitochondrial disease therapeutics.”
This work was supported by the German Research Foundation grant SCHA2182/1-1 and National Institutes of Health grants Q2 NS021328, MH108592, OD010944 as well as U.S. Department of Defense grants W81XWH-16-1-0401 and W81XWH-21-1-0128.
Schaefer et al, “Nicotinamide Riboside alleviates exercise intolerance in ANT1-deficient mice.” Mol Metab. Published online 2022 August 6. DOI: 10.1016/j.molmet.2022.101560.
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