Mitochondrial myopathies are a group of diseases affecting muscles caused by damage to mitochondria—small, energy-producing structures that serve as the cells’ “power plants.” These diseases often manifest with exercise intolerance as well as progressive muscle fatigue and weakness, especially in eye muscles, or progressive external ophthalmoplegia (PEO). However, no curative treatment currently exists for this group of diseases, but vitamin therapies may provide some improvement.

Pirinen and colleagues from the University of Helsinki published an article in Cell Metabolism on clinical trial data (NCT03973203) reporting that myocardial myopathy leads to low blood and muscle levels of nicotinamide adenine dinucleotide, a vital molecule involved in mitochondrial function. Importantly, they show that treatment with niacin—a vitamin B3 form and NAD+ precursor—improves NAD+ levels in muscle and blood, disease signs, and muscle strength and performance in human patients.

Can vitamin B3 forms alleviate mitochondrial myopathy symptoms?

NAD+ has important roles in regulating metabolism, and it’s roles in longevity, aging, and disease are under intense investigation, so far mainly in model organisms. Along these lines, the depletion of NAD+ has been proposed to promote aging and degenerative diseases in rodents. However, whether NAD+ depletion occurs in patients with degenerative disorders and whether NAD+ repletion improves their symptoms has remained open.

Interestingly, in a mouse model for mitochondrial myopathy, investigators previously observed that supplementation with an NAD+ precursor vitamin B3, nicotinamide riboside, prevented and delayed disease symptoms by increasing mitochondrial biogenesis. Vitamin B3 exists in a few different forms: niacin, nicotinamide, and nicotinamide riboside. It has been demonstrated to improve the function of diseased mitochondria in animal studies by increasing intracellular levels of NAD+.

“Our main question was whether NAD+ levels are depleted in mitochondrial dysfunction, as mitochondria are regulating NAD+ concentrations, and if so, whether NAD+ deficiency can be restored in the tissues of the patients,” said the investigators. So, Pirinen and colleagues tested whether niacin could recover dysfunctional mitochondria and rescue symptoms of mitochondrial myopathy. Of the vitamin B3 forms, they employed niacin because it has been used in large doses to treat hypercholesterolemia patients and has a proven safety record in humans.

Niacin repletes NAD+ deficiency in human muscle and blood

The research team supplemented PEO patients and healthy matched controls with a slowly increasing dose of niacin, from 250 mg/day up to 750 or 1000 mg/day for four months. They continued the follow-up of the treatment effect up to 10 months in patients. Pirinen and colleagues showed that adult-onset mitochondrial muscle disease causes NAD+ deficiency, or what’s called a myopathy-induced vitamin B3 deficiency. Blood NAD+ increased in all subjects, up to 8-fold, and muscle NAD+ of patients reached the level of their controls.

They then showed that NAD+ levels can be rescued by niacin. Niacin remarkably restored muscle and systemic NAD+. In the healthy subjects, niacin did not increase muscle NAD+, despite the 5-fold increase in the blood. “Our data implicate the potent effects of vitamin B3 forms on metabolism and present blood NAD+ analysis as a powerful tool to identify patients and individuals with NAD deficiency,” said the investigators.

(Pirinen 2020 | Cell Metabolism) Myocardial myopathy patients show systemic and muscle NAD+ depletion which can be rescued by niacin. The graphs show muscle (left) and whole blood (right) NAD+ content before and after niacin supplementation in controls (black) and progressive external ophthalmoplegia (PEO) patients (red). In both muscle and blood, there is a deficiency in NAD+ levels in PEO patients seen at the beginning of the study (0 months). After 4 months of niacin treatment, the levels of NAD+ in the muscle and blood of PEO increased. However, only the NAD+ levels in muscle of PEO patients recovered to similar levels as the healthy controls.

Niacin enhances mitochondria production and muscle strength in myocardial myopathy patients

The patient’s metabolism responded to niacin supplementation similarly. Some patients showed anemia tendency, while muscle strength and mitochondrial generation increased in all subjects. In patients, the muscle metabolite profile shifted toward controls and liver fat decreased even 50%.

Given niacin’s remarkable metabolic effects, Pirinen and colleagues explored whether it affected the performance of the patients. After 10 months of niacin, myocardial myopathy patients showed improved muscle strength, which differed by muscle groups. On average, patients had increases of 10-fold in abdominal muscles, 2-fold in back muscles, and 2.5-fold in upper extremities (shoulder and elbow flexion strength). The researchers only observed a small improvement in lower extremities (knee extension strength 1.1-fold) and the six-minute walking test.

(Pirinen 2020 | Cell Metabolism) Niacin improves muscle strength and performance. These graphs show the distance traveled during 6 min walk test (A) and performance of back muscle (B), abdominal muscle (C), repetitive shoulder muscle lift (D), elbow flexion (E) and knee extension (F) strength compared to baseline in controls and patients. The researchers saw improvements across the board in patients with myocardial myopathy upon niacin treatment.

“We demonstrate that niacin remarkably restores muscle and systemic NAD+ and provides metabolic and functional benefits for patients with mitochondrial myopathy, indicating that NAD+ deficiency contributes to disease progression,” said the investigators in the article.

This study underscores the potent role of vitamin B3 in metabolism. It also identifies NAD+ deficiency as a contributor to mitochondrial myopathy progression and suggests that a blood NAD+ test could serve as a tool to identify NAD+ deficiency. The researchers say that these findings point to the usefulness of niacin therapy for PEO patients.

(Pirinen 2020 | Cell Metabolism) Niacin treats systemic NAD+ deficiency and improves muscle performance in adult-onset mitochondrial myopathy. Mitochondrial myopathy patients have NAD+ deficiency in muscle and blood. Niacin is an efficient NAD+ booster in humans and improves muscle strength and fatty liver in mitochondrial myopathy. Niacin boosts muscle mitochondrial generation and oxidative phosphorylation (OXPHOS)—a major pathway that cells use for generating energy—in humans.

Will niacin be used as a treatment for mitochondrial myopathy in the future?

Future studies are needed to tell whether early treatment immediately after diagnosis might delay disease progression even further. “Our pilot study is a proof-of-principle of niacin effects on mitochondrial myopathy,” said the investigators in their article. Also, the optimal dose for mitochondrial myopathy needs to be determined as the dose chosen for niacin supplementation was based on its efficacy in hypercholesterolemia.