Measuring bioactive nitric oxide during exercise could help improve fitness, and this new device provides real-time data

The heart is the master dispatcher for our lifeblood. It has the crucial burden of balancing physiological economics during rest, during a ride, and while recovering. If the heart can’t pump enough blood to equal demand for nutrients and oxygen, fatigue sets in, you bonk, and sometimes, you have to quit. Rest and replenishment are the only salvation. 

It is well understood that the body’s managerial mechanisms run much deeper, especially during exercise. Governing a cyclist’s overall ability to continue putting out power during any type of effort are the cellular and molecular constituents produced and delivered alongside every contraction of the restless courier in our chest. Oxygen, glucose, fatty acids, lactate, hemoglobin, bicarbonate, nitric oxide — all are important, each playing a role in how well we are able to respond to the stresses of exercise. They also dictate how well the body can adapt and repair between exercise sessions.

We make an intentional point to try and measure and understand the importance of biomarkers and vitals in athletic training and performance, with the current boom in wearable technologies making it possible to deliver insights never previously fathomed. Though no lack of data exists, is there a best measure to understanding an athlete’s exercise capacity and fitness?

Being able to measure blood flow has been a decades-long quest in sports medicine. Exercise physiologists often focus on the mitochondria, bioenergetics, and oxygen consumption (VO₂) as a pathway to understanding someone’s performance capacity and upper limits. Coaches use biological outputs such as lactate and heart rate layered atop metrics like power to guide training strategy. The integration of all of these somatic informatics is rightfully based on what we know as best practice today.

But what are the true regulators and rate limiters of performance? We know that the ability to do work (ride a bike) is based on a few basic orderly factors:

1. Muscles need oxygen
2. and fuel (glucose, fatty acids)
3. to synthesize ATP
4. which is used to output mechanical energy
5. so that they can contract
6. and work (exercise) can be done.

But a crucial step is missing: the regulation of delivering oxygen and fuel. The body was divinely designed to compensate and adapt to changing conditions, and at the level of muscle oxygenation and work output, here is how that concept is applied. At the onset of exercise, a shift in blood flow must occur to ensure oxygen and nutrients are delivered where they are needed most — your working skeletal muscles, the heart, and brain, primarily. The ability to measure and understand how this happens is crucial. As it turns out, one molecule is inadvertently responsible, and without it, everything else is impossible. 

Hello, SNO.

Performance regulation: There’s a new kid in town.

Nitric oxide (NO) has been hailed as one of the most important regulators of cardiovascular health, impacting blood pressure, inflammation, and overall vascular function. It is a potent vasodilator, responsible for directing and improving blood flow to areas of the body where blood flow is needed most. This happens during periods of oxygen demand and supply mismatch, like exercise, and it happens almost immediately. The supplement market is booming with products that help athletes improve NO production, such as L-arginine, to help maximize blood flow to muscles during a workout.

All of this stated, the classic understanding of how NO is produced and directs blood flow is beginning to change, which inevitably impacts how we think of performance regulation. Let’s break it down. We know that:

1. Muscles need oxygen,
2. and oxygen is carried by hemoglobin in red blood cells.
3. Oxygen must be transferred from red blood cells to muscles 
4. so work (exercise) can be done. 

Further:

5. When exercise starts, 
6. muscles begin consuming oxygen at a higher rate.
7. A dip in available oxygen happens.
8. Oxygen is increasingly offloaded from red blood cells to try and match the new demand. 

Remember: supply must match demand. 

Now what? An economic dance ensues between red blood cells (where oxygen is carried), and the oxygen tension in the muscle itself. A newer discovery has explained how this interplay impacts overall dispersion of blood during a workout so muscles can be adequately fueled and exercise can continue, and it is meticulously regulated.

During conditions where oxygen tension in muscles (and therefore red blood cells) decreases, a nitric oxide derivative called S-nitrosohemoglobin (SNO-Hb) is also produced and offloaded by hemoglobin alongside oxygen. SNO-Hb, part of a group of compounds called S-nitrosothiols, or SNOs, dilates the tiny blood vessels in the muscle tissue itself (capillaries, arterioles). Blood flow increases, and oxygen delivery can now meet the heightened demand. This goes for nutrient delivery too, like increased need for fatty acids and glucose.

Why is measuring SNO helpful?

It could be hypothesized that many of the foundational benefits of exercise are due to these well-controlled increases in blood flow. There is a system-wide effect on the heart and brain, too. Further, there are adaptations to the cardiovascular system and blood profile in response to training. More exercise leads to more hemoglobin, a larger blood volume, and a greater and faster NO response. The latter specifically leads to a better blood flow response, and therefore improved oxygen and nutrient delivery. Theoretically, the same goes for bioactive NO derivative, SNO, at the tissue level. In this perspective, SNO is sitting in the driver’s seat and orchestrating it all.

Devices exist on the market today that measure oxygen saturation in muscles and other tissues (SmO₂ or tissue oximeters), but that only paints a partial picture of the impact certain types and intensities of exercise have on an individual. Being able to measure someone’s SNO response to exercise would offer the first look into the gatekeeper of muscle oxygenation. Why do we care? All of this impacts the ability for mitochondria to output adenosine triphosphate (ATP). It is also an indicator of muscular damage during injury and nourishment during rehabilitation. These processes all require oxygen.

Measuring SNO is specific, and it may indicate the readiness and effectiveness of exercise on a personalized level. It can be associative to overall VO₂, and oxygen consumption specific to the muscle (called mVO₂) as well. It may be an indicator of power output and capacity, and could also correlate to lactate efflux. Further, and most importantly, it can stand alone as its own measurement. As with anything truly new and disruptive, a lot of research needs to be conducted, but there is evidence indicating the usefulness of SNO as a novel biomarker to gauge fitness and performance.

How can we measure SNO? NNOXX has a device

There is a device available today that non-invasively measures SNO, plus muscle oxygenation (SmO₂) and muscle oxygen consumption (mVO₂) from a company called NNOXX. (Full disclosure: I have consulted with NNOXX on clinical and regulatory affairs.)  It’s the only device of its kind, delivering continuously streaming data that can be accessed at any point during a ride or workout. NNOXX helps athletes understand the efficiency and effectiveness of an exercise by measuring these performance indicators directly in exercising muscle, in real time.

One differentiating thing about these biomarkers is that they are exercise “blind,” meaning you can ride or you can lift, and you will still produce SNO and use oxygen, just not in the same way (a topic for a different article). The $299 NNOXX device can be used to make individualized assessments during many types of exercise — biking, lifting, and running, as examples — and only needs to be placed on the exercising muscle during your workout. 

So how can riders use NNOXX to help improve their cycling performance?

NNOXX provides a Performance Readiness Score

Muscle recovery can be impacted by insufficient calories, poor sleep, dehydration, overreaching, or even the onset of illness. NNOXX is differentiated because the biological assessments are measured and delivered in real-time based on rates of oxygenation and deoxygenation, plus the bioactive nitric oxide response while you’re exercising. All you have to do is a guided four-minute cycling protocol and the app will give you both a Muscle Readiness and Aerobic Readiness percentage tailored to your physiological status. You’ll be given a recommendation of how to proceed based on your score. You can also see a seven-day trend.

NNOXX can help you understand how well you performed compared to other rides or exercise sessions. 

The app provides individualized performance indicators, including a Power Index, Endurance Index, and Economy.  These indicators are based on your personal rates of muscle deoxygenation, reoxygenation and other factors, measured in real-time during your workout. After your workout is finished, you’ll receive your score for the day, your average range, and 60-day comparative trend. 

This feature is really useful if riders have regular routes or workouts, and they’re interested in seeing if they’re improving, especially when making changes to their routine (e.g. more sleep, additional interval sessions, changes in recovery or dietary habits, or longer rides). 

Further, users can potentially infer if a specific type of riding is best for them. For example, if the data shows you’re more efficient at climbing than previously thought, it may be something worth capitalizing on or integrating more often into your routine. The opposite can be a takeaway, too. If the app indicates you perform better doing power activities than long rides, you can use this to create a goal around improving your endurance.

What if I am new to mountain biking or cross-training and to improve my performance without hiring a coach or personal trainer? 

The NNOXX app provides an AI-guided coach to customize your ride or other workout to be the most effective and efficient. The output is based on the effects of your real-time SNO production. As data is aggregated, workouts can be compared and personalized to your individual physical performance to help maximize gains.

For a new-to-market device and a new biomarker, the metrics provided by the device do seem to be physiologically reliable and accurate. Because the data is provided continuously with relatively no lag, the information can easily be compared to other performance indicators. Users can see how their body is compensating for increases in cadence or terrain grade, as examples.

NNOXX recently released a feature that allows users to import their Strava and Peloton data into the High Performance Platform on their website. Comparisons between SNO and SmO₂ can be made alongside work, power, heart rate, and others on a single platform. 

Again, the SNO biomarker and associated performance indicators are new. Like most things in science and medicine, it takes time to build up a bank of clinical evidence that is trustworthy, and the data on SNO as a performance biometric promises to evolve as discoveries are made and information is added. The digital technology boom is allowing researchers and developers to change the landscape at an unmatched speed, and NNOXX is a great example of what I believe is a positive outcome of the race.

Sources

Premont, R. T., Reynolds, J. D., Zhang, R., & Stamler, J. S. (2020). Role of nitric oxide carried by hemoglobin in cardiovascular physiology: developments on a three-gas respiratory cycle. Circulation research, 126(1), 129-158.

Reynolds, J. D., Posina, K., Zhu, L., Jenkins, T., Matto, F., Hausladen, A., … & Stamler, J. S. (2023). Control of tissue oxygenation by S-nitrosohemoglobin in human subjects. Proceedings of the National Academy of Sciences, 120(9), e2220769120.