New Insights on Muscle Strength: The Role of Inhibiting an Enzyme that Hinders NAD+ Synthesis

Key Points:

• The scientists used a compound called 5-amino-1MQ to inhibit an enzyme called NNMT that plays a role in breaking down a precursor to NMN in the NAD+ synthesis pathway.
• Treating with 5-amino-1MQ improved grip strength better than exercise alone in aged mice.
• Compared to rigorous exercise training on its own, the addition of 5-amino-1MQ conferred sustained enhanced muscle performance, suggesting a reduced need for muscle recovery.

Deteriorating muscle strength and function as we get older lead to debilitating conditions like frailty, which can be life threatening. In fact, starting at age 50, people lose about 1% of their muscle mass and strength with each passing year, which gets progressively worse.

Now, published in Scientific Reports, Watowich and colleagues from the University of Texas Medical Branch show that treating with 5-amino-1MQ improves grip strength to a greater degree than rigorous exercise in aged mice. Moreover, the compound additively enhances the improvements in strength that come from vigorous exercise, and the data also suggests that it shortens muscle recovery time following bouts of vigorous exercise.

5-amino-1MQ acts as an inhibitor of an enzyme called NNMT that degrades a nicotinamide adenine dinucleotide (NAD+) precursor called nicotinamide, which is also a precursor of nicotinamide mononucleotide (NMN). Interestingly, although no human trials have been conducted to test its efficacy, at least a few clinics in the US provide oral doses of 5-amino-1MQ to their clientele. As such, even though the FDA has not approved its use, we can assume that some adults are already taking it. Along those lines, a quick online search does not show that the FDA has even classified 5-amino-1MQ as “generally recognized as safe,” which is the first step in making it available as a supplement.

An NNMT Inhibitor Increases Strength and Alleviates the Need for Muscle Recovery

To test the effects of 5-amino-1MQ, the Texas-based research group divided aged mice into four groups: one sedentary group with low activity, another sedentary group given the compound, a group that underwent rigorous exercise without treatment, and another that underwent exercise and treatment. Upon measuring grip strength, the researchers found that treatment on its own in sedentary mice increased grip strength by about 25%, compared to exercise alone increasing grip strength by about the same percentage. Moreover, when combined with rigorous exercise, 5-amino-1MQ treatment increased grip strength by about 60%. These findings suggest that combining the treatment with exercise produces an additive enhancement of muscle strength better than either exercising or using the treatment alone.

To compare how treating with 5-amino-1MQ in addition to exercise training compares to training alone on endurance, Watowich and colleagues measured running distances over about a two-month span. They found that over this period, daily running distances increased initially for the group that underwent exercise training but then tapered off toward similar distances run before any training, which may have been due to muscle fatigue. Intriguingly, when 5-amino-1MQ treatment was added to the training routine, daily distances run not only increased but tapered off to a much lesser extent than that seen with exercise training alone. This finding suggests that the NNMT-inhibiting compound alleviates the need for muscle recovery following vigorous exercise.

The additive effects of increased strength and endurance from 5-amino-1MQ suggest that the compound influences molecular pathways differently from exercise training. In that sense, if 5-amino-1MQ had effects on the same molecular pathways as exercise, aged mice treated with the compound that also exercised would not receive much of an effect from the treatment.

To test and confirm that 5-amino-1MQ acts on different pathways than exercise, Watowich and colleagues measured levels of a slew of proteins following treatment. They found that, as expected, 5-amino-1MQ altered the levels of proteins that were different from those seen with exercise training alone. In fact, among mice that underwent exercise training, the majority of the proteins with changed levels from adding 5-amino-1MQ treatment did not coincide with those that went untreated. This finding suggests that the NNMT-inhibiting compound has effects on pathways different from exercise training on its own and that taking it does not work the same way as exercising regularly.

Moreover, the buildup of fats in muscle cells is associated with lower insulin sensitivity in adults who do not exercise regularly, suggestive of reduced muscle quality. To test how 5-amino-1MQ affects muscle cell fat levels, Watowich and colleagues measured them. They found that sedentary mice treated with 5-amino-1MQ and mice that underwent vigorous exercise had significantly lower levels of muscle cell fats, suggesting improved muscle quality.

Also, although there was a trend toward lower muscle cell fats when combining the NNMT-inhibiting compound with exercise, the decline was not significant. It remains unclear why the addition of 5-amino-1MQ to exercise training produced a non-significant decline in muscle cell fats, but perhaps future studies attempting to replicate these findings will find significance if they include more mice in their experiments.

The NNMT Inhibitor May Enhance Muscle Performance Through Increasing NAD+

The study’s findings that the NNMT inhibitor, 5-amino-1MQ, improves muscle strength and endurance in aged mice may come from boosting NAD+ levels through increasing cellular levels of its precursor, nicotinamide. To find whether this is true, future studies could examine whether genetically modifying mice so that they cannot synthesize NAD+ as well has any effects on 5-amino-1MQ enhancing muscle strength and endurance. If inhibiting NAD+ synthesis has an adverse effect on 5-amino-1MQ’s muscle-enhancing effects, this would show that, indeed, the compound likely works through increasing NAD+ levels.

Moreover, future studies could examine whether adding other NAD+ precursors like NMN improves the muscle-enhancing effects of 5-amino-1MQ. If they do, this would also add evidence that this NNMT inhibitor improves muscle performance through increasing NAD+ levels.

Also, the study has some limitations, such as the fact that the researchers only used aged female mice for their experiments. Future studies of the compound should use male mice to confirm that its effects are not sex specific.

What’s more, the study only tested treatment for approximately two months. More research is required to determine the long-term effects and potential risks of 5-amino-1MQ treatment. Further studies also need to find whether 5-amino-1MQ’s effects last after ceasing treatment. Last, human studies are necessary to first determine the safety of 5-amino-1MQ and then its efficacy. As mentioned, some clinics have already started applying this NNMT inhibitor to humans, even though the FDA has made no ruling on its safety, making human trials paramount. If human trials with the compound show safety and efficacy, NNMT inhibitors like 5-amino-1MQ could serve to prevent and/or slow age-related muscle deterioration in humans, a tantalizing prospect.