Background:
NAD⁺ (nicotinamide adenine dinucleotide) is a critical coenzyme involved in cellular metabolism and energy production. Its decline has been associated with aging and degenerative diseases, particularly mitochondrial myopathies—a group of disorders caused by dysfunctional mitochondria. This study aimed to investigate whether niacin (vitamin B3), an NAD⁺ precursor, can reverse systemic NAD⁺ deficiency and improve muscle performance in patients with adult-onset mitochondrial myopathy.
Study Design and Methods
- Participants:
- 5 adult-onset mitochondrial myopathy patients (with progressive external ophthalmoplegia) and 8 age- and sex-matched healthy controls were enrolled.
- Intervention: Patients received escalating doses of niacin up to 750–1000 mg/day for 10 months. Controls received the same treatment for 4 months.
- Primary Measures:
- Blood and muscle NAD⁺ levels
- Muscle strength and performance
- Mitochondrial biogenesis and histology
- Body composition and fat distribution
- Muscle and blood metabolomics
- Statistical Analysis: Various tests including Friedman non-parametric ANOVA, Wilcoxon test, and two-way ANOVA with Dunnett’s multiple comparisons were used. P-values were reported for significance thresholds.
Book NAD+ session
Key Findings
1. Restoration of NAD⁺ Levels
- Blood NAD⁺: Increased 8.2-fold in patients (p < 0.001), reaching levels comparable to controls.
- Muscle NAD⁺: Normalized in patients after 10 months.
- NAD⁺ metabolite levels, including NAM and ADP-ribose, also increased significantly, indicating effective conversion through the salvage pathway.
2. Muscle Strength and Performance
- Significant improvements in muscle strength:
- Abdominal muscles: ~10-fold increase
- Back muscles: ~2-fold
- Upper extremities (shoulder, elbow): ~2.5-fold
- Lower extremities (knee extension): ~1.1-fold
- 6-minute walk test: Slight improvement
- Ocular muscle strength: No improvement due to irreversible atrophy
- Lactate levels: Decreased after exercise (p < 0.05), reflecting improved muscle metabolism
- Patient-reported outcomes: Some noted better exercise tolerance, fewer muscle cramps, and improved sleep; however, average quality of life scores remained stable.
3. Mitochondrial Biogenesis and Function
- Histological improvements:
- Decreased number of COX-deficient, SDH-positive muscle fibers (markers of mitochondrial dysfunction)
- Increased mitochondrial mass and COX activity in both patients and controls (p < 0.05)
- Persistent abnormalities:
- No change in mtDNA deletions or mitochondrial ultrastructural damage (e.g., distorted cristae)
- Conclusion: Niacin enhanced mitochondrial biogenesis but did not reverse genetic mitochondrial damage.
4. Body Composition and Fat Distribution
- Muscle mass: Increased in both patients and controls
- Fat mass:
- Liver fat: Decreased by 50% (p < 0.01)
- Visceral fat: Decreased by 25% (p < 0.05)
- Subcutaneous fat: Unchanged
- Energy metabolism: Trend toward increased energy expenditure
- Adiponectin: High molecular weight form significantly increased and inversely correlated with liver fat content (p < 0.01).
5. Metabolic Reprogramming
- Niacin reprogrammed the muscle metabolome:
- Restored purine and pyrimidine synthesis intermediates (e.g., IMP, AMP, cytidine, deoxycytidine)
- Increased levels of amino acids (e.g., taurine, creatine) in muscle
- Plasma amino acid levels decreased, suggesting enhanced muscle uptake
- Creatine and creatinine levels normalized, supporting improved ATP recycling and muscle bioenergetics (p < 0.01)
- Significant increase in taurine, important for muscle contraction and cellular signaling.
6. Lipoprotein and Glucose Metabolism
- HDL2b (anti-atherogenic particles): Increased in patients (p < 0.05)
- LDL and VLDL (triglyceride-rich particles): Decreased in patients after 10 months
- Fasting glucose: Increased in both groups
- Insulin and C-peptide: Elevated in controls only
- HbA1c: Unchanged, suggesting no long-term glycemic disturbance
- Liver enzymes: Normal, indicating hepatic safety.
7. Hematologic Effects
- Erythrocyte counts and hemoglobin: Slight decrease in some patients, though remained within normal range
- Vitamin B12: Transient decrease; one patient received supplementation
- Plasma bilirubin: Unchanged, ruling out hemolysis as a cause
- Clinical note: Monitor hemoglobin and red blood cell parameters during NAD⁺-boosting therapy.
Conclusion
This clinical trial provides strong evidence that high-dose niacin supplementation (750–1,000 mg/day) is an effective NAD⁺ booster in humans with adult-onset mitochondrial myopathy. It successfully normalized systemic NAD⁺ levels, improved muscle strength, enhanced mitochondrial biogenesis, reduced hepatic fat, and favorably reprogrammed muscle metabolism. Although structural mitochondrial damage persisted, the functional improvements suggest therapeutic benefit. Some hematologic monitoring is warranted due to observed changes in erythrocyte parameters.
These findings open the door for larger clinical studies and support the potential of NAD⁺-repletion therapy in degenerative mitochondrial diseases.
For full details, refer to the original article: https://pubmed.ncbi.nlm.nih.gov/32386566/
