MOTS-C: The “Exercise Replacement” Peptide

Jay Campbell

By Jay Campbell

January 28th, 2021

 

Have you ever wondered if humanity will reach the point where you can take a pill and immediately receive all the amazing benefits of exercise?

We are nowhere near the point where all of the benefits of physical activity can be jam-packed into a single pharmaceutical drug, although many people are trying to achieve this state of zero-effort utopia:

“The promise is enormous—such medications could be a boon to people whose physical activity is limited by medical conditions or injuries.

They could provide a head start for people who are beginning an exercise program.

They could also confer the health benefits of exercise on healthy people who can’t fit physical activity into their schedules or just don’t want to get off the couch.”

Until this magical trillion-dollar drug exists, there’s a naturally-produced peptide in your body that comes close: MOTS-C.

When you inject this peptide into your body, there are numerous benefits you can expect to experience: Increased energy levels, greater fat loss, a longer lifespan, protection against age-related diseases, and so much more.

But how exactly does MOTS-C work to deliver all of these positive outcomes?

And where can you get your hands on “injectable” MOTS-C?

This article will definitely answer all of those questions, so keep reading!

What is MOTS-C?

MOTS-C (mitochondrial open-reading-frame of the twelve S rRNA-C) is a 16-amino-acid peptide that is naturally produced in your body by the mitochondria in your cells.

On a broader scale, the peptide is located in various organs of your body, such as the liver, brain, and muscle tissues.

Believe it or not, mitochondria have their OWN DNA, and within the “mitochondrial DNA” (mtDNA) are short open reading frames (sORFs) that can be used to encode and produce peptides.

In this sense, MOTS-C would be referred to as a “mitochondrial-derived peptide” (MDP).

(For more background information about mitochondria and the role they play in the body, read this slideshow presentation)

And as it turns out, MDPs like MOTS-C play significant roles in managing your metabolism:

“Considering that mitochondria are the single most important metabolic organelle, it is not surprising that these MDPs have metabolic actions. MOTS-c has been shown to target the skeletal muscle and enhance glucose metabolism.

As such, MOTS-c has implications in the regulation of obesity, diabetes, exercise, and longevity, representing an entirely novel mitochondrial signaling mechanism to regulate metabolism within and between cells”

MOTS-C has quite the interesting origin story, as its discovery was primarily implicated in treating obesity and diabetes:

“Research by Pinchas Cohen and his colleagues at the Leonard Davis School of Gerontology at the University of Southern California provides evidence that mitochondria play a key role in signaling and in energy production. 

The first studies on MOTS-c were conducted on obese mice. They showed that the peptide helped boost glucose metabolism even when the mice were fed a high fat diet. These preliminary studies show evidence for improved control over blood sugar levels for those with type 2 diabetes and obesity”

All of this changed in 2015, when the media started hyping up MOTS-C as an “exercise in a bottle” peptide:

“Scientists at the USC Leonard Davis School of Gerontology have discovered a new hormone that fights the weight gain caused by a high-fat Western diet and normalizes the metabolism – effects commonly associated with exercising.

Hormones are molecules that act as the body’s signals, triggering various physiological responses. The newly discovered hormone, dubbed “MOTS-c,” primarily targets muscle tissue, where it restores insulin sensitivity, counteracting diet-induced and age-dependent insulin resistance.

…To test the effects of MOTS-c, the team injected the hormone into mice fed a high-fat diet, which typically causes them to grow obese and develop a resistance to insulin. The injections not only suppressed both effects in mice, they also reversed age-dependent insulin-resistance, a condition that precedes diabetes.”

So the idea is quite straightforward: Inject MOTS-C into your body and you can stimulate the positive changes induced by vigorous exercise!

How Does MOTS-C Work?

MOTS-C primarily exerts its effects on energy metabolism through the activation of AMP-activated protein kinase.

More specifically, MOTS-C works similarly to a popular drug known as methotrexate:

“MOTS-c targets the skeletal muscle and acts on the folate cycle (one carbon pool) and inhibits the directly tethered de novo purine biosynthesis pathway. This leads to the accumulation of the de novo purine synthesis intermediate AICAR that is also a potent activator of the metabolic regulator AMPK, thus partially mediating the metabolic effects of MOTS-c.”

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And through a series of downstream reactions, MOTS-C delivers the “weight loss” effects of exercise:

“The AMPK also inhibits the Aceti-CoA – Carboxilase, which its function is transforming Acetil-Coa in Malonil-Coa – and this last one performs an allosteric inhibitory effect in the Palmitoil-Transferase 1. So, when AICAR inhibits Acetil-CoA-Carboxilase, it allows that more fatty acids enter in the mitochondria and be available for the β-oxidation.

These catabolic effects combined increase the lipolysis, reduce the lipogenesis and increase the reception of glucose.”

While there’s a lot more to this mechanism with respect to intricate details about each and every step of the cascade reaction, this is all you need to know about how MOTS-C works in the body.

It is through this mechanism that MOTS-C increases exercise capacity and has a reputation for being an “exercise mimetic” in the scientific community.

Top 6 Health Benefits of MOTS-C

MOTS-C goes far beyond being a mere “exercise mimetic” – with just over 55 studies published on PubMed between 2015 and 2021, there’s been a growing amount of interest in discovering its other anti-aging properties.

So with that said, here are the top 6 health benefits of using the peptide MOTS-C…

MOTS-C Is Very Potent For Weight/Fat Loss

When it comes to adiposity reduction (i.e. burning fat), MOTS-C is quite effective:

“In this study, we observed that the level of MOTS-c in serum decreased after cold stress.

MOTS-c treatment enhanced cold tolerance and reduced lipid trafficking to the liver.

In addition, MOTS-c dramatically upregulated brown adipose tissue (BAT) thermogenic gene expression and increased white fat “browning”.

One testimonial on Reddit was especially captivating, as the user claimed it was the peptide alone that allowed him to achieve significant weight loss:

“…where I was more surprised was a fat loss esp around my midsection and love handles, some in my face. I feel lighter.

Roughly I dropped from 18% body fat to 15% by day 15, if I’m to trust my scale (not the best way to measure fat loss) No changes in diet or duration and intensity of exercise.

My pants are starting to fall down and getting some compliments from my spouse”

On top of that, numerous peptide clinics (here and here) also vouch for MOTS-C as a powerful fat loss peptide.

In a Cell Metabolism review of several studies, a few interesting observations were made about mice who were treated with MOTS-C and fed a variety of diets:

“Although MOTS-c treatment had no effect on body weight in mice fed a normal diet, it remarkably prevented obesity when administrated to mice fed a high-fat diet [HDF]. This difference in body weight was not attributed to food intake, as caloric intake was identical between the groups.

Additionally, MOTS-c treatment prevented HFD–induced hyperinsulinemia, indicating improved glucose homeostasis

Hepatic lipid accumulation was dramatically reduced in HFD-fed mice treated with MOTS-c . Notably, MOTS-c promoted AMPK activation and GLUT4 expression in the skeletal muscles of HFD-fed mice

“…These studies suggest that MOTS-c prevents HFD-induced obesity by increasing energy expenditure, including heat production, and improving glucose utilization and insulin sensitivity.

Reduced fat accumulation may be a result of robust carbohydrate usage that reduces fatty acid synthesis, but the possible involvement of increased fatty acid oxidation, as observed in vitro, would need detailed examination before being ruled out”

(Source)

Contrary to what you may think, it’s the improved regulation and usage of glucose (i.e. carbohydrates) that allows MOTS-C to be a powerful agent for combatting obesity:

“In animal models of obesity and diabetes, researchers have found that certain metabolic pathways are overactivated. These include the breakdown of fats and energy sources other than glucose. The detection of products and by-products of this breakdown serve as clues that normal, healthy metabolism has gone astray.

Collectively, the results indicate that MOTS-c improves the efficiency with which mice can process glucose. That has positive implications for keeping fat from accumulating in muscle and for maintaining an overall healthier lifestyle.”

Moreover, the fact that MOTS-C targets the skeletal muscle while enhancing the metabolism of glucose explains why it may be so helpful for treating aging-related diseases:

“The results showed that MOTS-c treatment decreased myostatin levels in plasma and skeletal muscle (p<0.05). However, no alterations were detected in heart muscle… MOTS-c treatment leads to a decrease in the systemic and tissue specific levels of myostatin, which may block the weakening of muscle strength”

If you want to dive deeper into the science of how this all works, here’s an educational YouTube video that shows exactly how metabolic dysfunction in obese mice can be fixed with MOTS-C:

 

MOTS-C Increases Your Energy Levels

One of the most talked-about benefits of MOTS-C amongst peptide experts is its ability to increase your energy levels, especially for endurance during cardiovascular exercise.

So much so to the point where there is a mass spectrometry method developed to help detect MOTS-C in doping samples, and you’re about to see why…

This brand-new study from the University of Southern California was literally released YESTERDAY and shows how powerful MOTS-C can be in increasing your body’s capacity for maximum physical performance.

Online magazine New Atlas summarizes the main findings of the study in three separate parts:

PART 1 – MOTS-C DETECTION IN HUMANS:

The team had 10 healthy (but sedentary) male human volunteers, aged in their 20s, exercise on a stationary bike, then rest for four hours. The researchers took samples of their skeletal muscle and plasma before, during and after the exercise, and after the rest, to measure levels of MOTS-c.

“…in skeletal muscle the MOTS-c levels significantly increased by 11.9 times after exercise, and although they trended back towards the baseline over time, levels were still higher than previously even after the four-hour rest. MOTS-c in plasma was also elevated by 50 percent after exercise, and dropped to baseline faster.”

PART 2 – MOTS-C DETECTION IN MICE:

“…the team next investigated the hypothesis that exercise triggers the release of MOTS-c, and that the hormone itself is responsible for some of the physical benefits associated with exercise.

The researchers injected MOTS-c into mice of three different ages – two-month-old young mice, 12-month-old middle-aged mice, and 22-month-old elderly mice – for two weeks, then had them perform physical challenges.

In all age groups, the treated mice performed significantly better than controls in tests on a rotating rod and a treadmill. Intriguingly, the elderly mice appeared rejuvenated by the treatment, improving their grip strength, gait and walking abilities”

PART 3 – MOTS-C AFFECTS BODY COMPOSITION

“In a follow-up experiment, the team investigated how the MOTS-c treatment affected mice under metabolic stress. Mice were fed a high-fat diet then treated with MOTS-c twice a day, at different dosages. After seven days of treatment, the animals had improved insulin sensitivity, which lessens their risk of diabetes. The animals also gained less weight on the high-fat diet than untreated mice.

After 10 days, mice on the higher dose of MOTS-c were running further and burning more energy than untreated ones. In fact, 100 percent of the higher-dose mice were able to complete the final treadmill test – sprinting 23 m (75 ft) per minute – whereas only 16.6 percent of mice in the lower dose and control groups managed the feat.”

While the first and third parts confirmed what was already proved in the existing medical literature, the second part was the most surprising finding.

Especially considering that the older mice treated with MOTS-C were able to outrun the untreated middle-aged mice, effectively doubling their running capacity!

MOTS-C Improves Insulin Sensitivity

For the diabetics reading this article, MOTS-C may be the peptide y0u’ve been looking for all along.

But before I get into why that’s the case, let me start off with a harsh warning to mothers and fathers around the world…

If you have younger male children who are obese, you are setting them up for a lifetime of harmful insulin resistance:

“MOTS-c levels were significantly decreased in the obese group compared with the control group. After classification by sex, MOTSc levels were significantly decreased in obese male children and adolescents compared to their counterparts, while they were comparable between the obese and healthy female subjects

“Circulating MOTS-c levels were decreased in obese male children and adolescents and correlated with markers of insulin resistance and obesity”

Not to mention that mitochondrial-derived peptides such as MOTS-C are heavily down-regulated in adults with type 2 diabetes (i.e. MOTS-C levels are much lower).

NOTE: One study sugggests that higher levels of MOTS-C are associated with better insulin senstivity in leaner individuals, yet no correlation exists in obese individuals

And surprise – lower MOTS-C levels are connected to higher severity of obstructive sleep apnea (not to mention a higher body mass index)!

A 2020 review of numerous MOTS-C studies found that the peptide was able to effectively tackle three types of insulin resistance:

  • Aging-associated insulin resistance – Increases glucose uptake in skeletal muscles in aged mice.
  • High-fat diet (HFD)-insulin resistance – Increases insulin sensitivity in HFD-fed mice, increases GLUT-4 expression in skeletal muscle in HFD-fed mice (Source)
  • Obesity-associated insulin resistance – Plasma MOTS-c levels are lower in obese male children and adolescents and negatively correlated with markers of insulin resistance and obesity.

For more information, I highly recommend reading two articles I’ve previously written on the importance of insulin sensitivity for improved body composition and better health.

MOTS-C Directly Enhances Mitochondrial Health

Since MOTS-C is directly derived from mitochondrial DNA, you would imagine that it plays some sort of pivotal role in improving mitochondrial health.

One important role of MOTS-C involves improving the rate of mitochondrial biogenesis:

“Mitochondrial biogenesis is the process by which cells increase mitochondrial mass [i.e. the division and growth of mitochondria that already exist]. It was first described by John Holloszy in the 1960s, when it was discovered that physical endurance training induced higher mitochondrial content levels, leading to greater glucose uptake by muscles”

“The capacity for mitochondrial biogenesis has been shown to decrease with age, and such decreased mitochondrial function has been associated with diabetes and cardiovascular disease. Aging and disease can induce changes in the expression levels of proteins involved in the fission and fusion mechanisms of mitochondria, thus creating dysfunctional mitochondria.”

Another way through which MOTS-C upregulates mitochondrial function at the cellular level is through protection against reactive oxygen species (i.e. free radicals) that form as a by-product of energy production:

“In addition, MOTS-c can stimulate your mitochondria… [via] gene expression to increase their production. All this results in more ATP production, which equates to more energy and less fatigue. Moreover, if you can boost your energy productions as you age, you may have a more active life and potentially live longer too”

“In essence, you are simply using MOTS-c, which is actually produced by the mitochondria’s own DNA, to protect the mitochondria from age-related degradation. The result is that you get a boost of energy production from your own mitochondrial powerhouses.”

In other words, MOTS-C can enhance the mitochondria’s ability to react to metabolic stresses and therefore correct metabolic imbalances.

This is why many of the previously described benefits – fat loss, more energy, improved insulin senstivity – are all possible with MOTS-C.

MOTS-C Can Help You Live a Longer, Healthier Life

According to a systematic review published in 2020 about the role of mitochondrial-derived peptides in age-related diseases, your body’s MOTS-C levels tend to gradually decline over time:

“MOTS-c levels also decrease with age in humans. In middle-aged (45–55 years) and old-aged (70–81) individuals, circulating MOTS-c levels were 11% and 21% lower compared with those in younger individuals (18–30 years), respectively”

“The decline of MOTS-c levels during aging and the correlation between MOTS-c levels and pathological conditions suggest that higher MOTS-c levels may protect against age-related diseases. Indeed, MOTS-c administration to mice provides beneficial effects in multiple pathological conditions such as insulin resistance, ovariectomy-induced metabolic dysfunction, and bone loss.”

In fact, some researchers speculate that a specific genetic alternation within MOTS-C explains why Japan has a much higher average lifespan compared to the rest of the world

“Although more research is needed, we suggest that the m.1382A>C polymorphism located in the MOTS‐c encoding mtDNA, which is specific for the Northeast Asian population, may be among the putative biological mechanisms explaining the high longevity of Japanese people.”

“Among long‐lived individuals, those who reach exceptional longevity (EL, i.e., centenarians (≥100 years) and supercentenarians (SCs, ≥110 years)) are arguably the paradigm of successful aging… Japan has clearly the longest life expectancy in the world, as well as the highest number of SCs, as we recently reviewed.”

MOTS-C Provides Numerous Anti-Aging Benefits

MOTS-C has also been studied for other benefits related to longevity and lifespan, although not to the same extent as the health benefits previously described.

But I do feel they are important to highlight as the peptide is still being studied to this day, so here is where the “science” stands as of this writing:

Overall, MOTS-C is a therapeutic peptide that is newer to the medical field but shows incredible potential in helping people increase bother their healthspan and their lifespan.

The BEST Dose of MOTS-C for Improved Endurance & Fat Loss

I usually offer a blanket recommendation for dosing peptides, but I’m going to make an exception for MOTS-C.

Because truthfully, the best MOTS-C dose for enhanced fat loss and better endurance is still up in the air.

So for this reason, I’m going to share various protocols that have been suggested by some of the top peptide experts in the world:

Ben Greenfield in his book Boundless: 10 mg of MOTS-C injected once a week, ideally right before endurance exercise for the added mitochondrial benefit, can be repeated for up to 10 weeks in a row every year

Dr. William Seeds in his book Peptide Protocols, Volume 1: 5 mg of MOTS-C injected subcutaneously 3 times per week on a Monday-Wednesday-Friday schedule for 4-6 weeks, followed by a once-a-week dose of 5 mg for 4 weeks.

Dr. Rob Kominiarek: 10 mg of MOTS-C injected subcutaneously into the abdomen once a week for 4 weeks straight, followed by a second 4-week cycle within a 12 month period.

Yours truly: I’ve experimented with 2 mg of MOTS-C every third day, and 5 mg all at once.

I personally recommend this peptide in the morning to avoid disturbing sleep, plus it provides a noticeable energy boost within 30 minutes of administration. 

And while I cannot confirm this 100%, some MOTS-C users are claiming that the peptide degrades very rapidly upon being constituted due to its high level of instability (50% at 2 hour and 90% at 3 hours, according to one Reddit user).

For that reason, you might consider injecting the MOTS-C peptide immediately after it has been prepared.

MOTS-C Side Effects and Safety Profile

To my knowledge, MOTS-C is very safe and has not been proven to have any side effects.

This has been confirmed by a health clinic in Springfield, Missouri that frequently uses MOTS-C as a part of their “accelerated fitness programs”:

“Because peptide therapy is used in conjunction with lifestyle and diet changes, we typically expect patients to notice a difference in their shape or weight between 4 weeks to 3 months of beginning their program.

Being a peptide derived from the mitochondria, MOTS-c works to restore homeostasis with no side effects. During your consultation, your provider will briefly review your medical history, goals, and current medications and supplements to ensure your accelerated fitness program is developed safely and successfully.”

Then again, the MOTS-C peptide has yet to be clinically studied in human subjects (as you saw earlier, all of the available studies are done on either mice or cell cultures).

The very few biohackers who have attempted to experiment with MOTS-C report some of the following side effects

Based on my limited experience with using MOTS-C, I can confidently say the following…

Some people respond well to it, but those who are leaner and have stronger (i.e. more up-regulated) mitochondrial activity usually don’t.

At the end of the day, biochemical individuality is always the ultimate determinant for whether you will respond effectively to MOTS-C. 

The #1 Source for Pharmaceutical-Grade MOTS-C

As a research chemical, it can be extraordinarily difficult to find a legitimate vendor who will sell you pharmaceutical-grade MOTS-C. 

Fortunately for you, I’ve done the hard work of locating a supplier who exceeds expectations for peptide quality and purity. 

That vendor’s name is Limitless Life Nootropics and you can reliably source MOTS-C from them, along with any other peptide or nootropic available in their store. 

Use code JAY15 to get 15% off your order!

Unlike 99% of vendors in existence, all peptides are independently tested by a third-party analytical laboratory before they are made available for purchase

Additional Reading Resources for MOTS-C

I’ve compiled all of the available information about MOTS-C into this article, which was not a difficult feat considering how little information is available.

However, some of you may still want to explore this therapeutic peptide in further detail.

So without further ado, here are some additional reading resources for learning more about MOTS-C…

Dr. Eric of PRIME X has a two-part video series (Part 1, Part 2) that dives deep into the science of MOTS-C and how it works in the human body.

InfiniPulse has a scientific overview of all the bodily processes MOTS-C is directly involved in.

And as always…

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If you want more game-changing intel on peptides – new ones not featured on this site, where to source them, and the best protocols for using them – join the Elite ranks of The Optimized Tribe!

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