Nicotinamide riboside alleviates exercise intolerance in ANT1-deficient mice.
Mol Metab
; 64: 101560, 2022 10.
Article
in En
| MEDLINE
| ID: mdl-35940554
ABSTRACT
OBJECTIVE:
Mitochondrial disorders are often characterized by muscle weakness and fatigue. Null mutations in the heart-muscle adenine nucleotide translocator isoform 1 (ANT1) of both humans and mice cause cardiomyopathy and myopathy associated with exercise intolerance and muscle weakness. Here we decipher the molecular underpinnings of ANT1-deficiency-mediated exercise intolerance.METHODS:
This was achieved by correlating exercise physiology, mitochondrial function and metabolomics of mice deficient in ANT1 and comparing this to control mice.RESULTS:
We demonstrate a peripheral limitation of skeletal muscle mitochondrial respiration and a reduced complex I respiration in ANT1-deficient mice. Upon exercise, this results in a lack of NAD+ leading to a substrate limitation and stalling of the TCA cycle and mitochondrial respiration, further limiting skeletal muscle mitochondrial respiration. Treatment of ANT1-deficient mice with nicotinamide riboside increased NAD+ levels in skeletal muscle and liver, which increased the exercise capacity and the mitochondrial respiration.CONCLUSION:
Increasing NAD+ levels with nicotinamide riboside can alleviate the exercise intolerance associated to ANT1-deficiency, indicating the therapeutic potential of NAD+-stimulating compounds in mitochondrial myopathies.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Physical Conditioning, Animal
/
Pyridinium Compounds
/
Mitochondrial Myopathies
/
Niacinamide
/
Adenine Nucleotide Translocator 1
/
NAD
Limits:
Animals
Language:
En
Journal:
Mol Metab
Year:
2022
Document type:
Article
Affiliation country:
United States