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EvoMuse TopMuscle™ Write-Up
You are now entering the realm of a product many years in development. The quest for physique enhancement fuels an entire industry, with false solutions offered en masse. The ability to target certain muscles for growth, whether due to musculoskeletal lag, or to help accelerate growth all over, is something that's been attempted a few times but always ending in disappointment.
For TopMuscle™, our researchers spent hundreds of hours exploring all of the growth signaling (anabolic) pathways that have been delineated. While the one that many people are familiar with, mTOR, is generally best tapped via dietary manipulation (through amino acids like leucine and its metabolites as we covered in our Strafe™ product), there are many more than can be triggered at a local level, resulting in optimization of muscle growth in a site-specific manner.
Ingredients and Function
Apigenin
Apigenin is a flavone found in a variety of fruits, vegetables and herbs, as well as wine, beer, chamomile tea, and Gingko biloba.
This flavone has been shown to promote skeletal muscle growth as well as myogenic differentiation (the process of converting a less specialized cell into a muscle cell). It does this through multiple pathways (the Prmt7-PGC1a-GPR56 pathway and the Prmt7-p38-MyoD pathway, for the nerds out there) (1).
In a 2017 study, overfed mice were given apigenin and compared to a control group without apigenin. The supplemented group had less fat accumulation, lower inflammatory cytokines, and increased levels of fat-free mass. They also showed reduced expression of muscle atrophy-promoting genes, as well as an increase in exercise capacity through upregulated mitochondrial function and biogenesis (2).
In summary, apigenin should promote muscle growth, muscle cell differentiation, reduced fat gain, and increased exercise capacity.
Alpha-Terpineol
Alpha-Terpineol is an alcohol, included in TopMuscle™ to help disrupt the lipid bilayer of the stratum corneum and epidermis (the outermost layers of the skin). This enhances penetration and delivery of certain ingredients topically, like epicatechin, and allows them to quicky penetrate into the underlying muscle without being picked up sytemically (3).
Gibberellic Acid
Gibberellic acid is an extremly potent hormone found in plants, responsible for promoting and regulating growth in those plants. For those of us who aren’t plants, we have good news. Gibberellic acid has also been shown to increase growth in animals, by enhancing the activity of a growth related enzyme called guanylate cyclase (4).
GA has also been shown to increase 3b-HSD and 17b-HSD enzymes for greater conversion of DHEA to testosterone, as well as Steroidogenic Acute Regulatory Protein (StAR) and Androgen Binding Protein (ABP). This results in elevated testosterone, which earned it a tag as being an “inducer of steroidogenesis” (5).
In summary, GA targets natural testosterone boosting, as well as non-hormonal routes of muscle growth.
Epicatechin
This ingredient has become quite popular in the past few years with regards to muscle growth, and for good reason. It appears to increase size and strength, and quickly. Strength increases have been documented in research after only seven days of use (6).
Epicatechin has been shown to decrease myostatin (and favorably modulate plasma follistatin:myostatin ratios), which is one of the main governors of muscle growth. It also increases skeletal muscle capillarity, increases mitochondrial biogenesis, and other markers of muscle growth (6), (7), (8), (9).
In summary, Epicatechin decreases myostatin, enhances muscle growth, and increases strength.
Stearoyl Vanillyamide
SV is a non-pungent analogue of capsaicin, which is the active component of chili peppers.
One purpose of including SV in our formula relates to Heat Shock Proteins, or HSPs.
Quick primer on HSPs (taken from our BMP 2.0 write-up):
When the body undergoes heat stress (like during exercise), the muscle cells have to control potential damage with HSPs. Often referred to as intracellular “chaperones”, they’re basically molecules that act as a clean-up crew to facilitate protein transport, prevent mishaps during protein folding, and protect against protein denaturation (10), (11), (12). They have also been shown to improve insulin sensitivity, reduce oxidative stress, inhibit inflammatory pathways, and enhance the metabolic characteristics of muscle cells (13).
Take home point, anything that increases specific HSPs will likely speed up recovery and muscle hypertrophy.
It turns out that TRPV channels are intricately and favorably linked with HSPs, in the sense that activating TRPV receptors initiates HSP activation (which makes sense since TRPV1 is activated in the presence of extreme heat levels such as when the body is being physically burned—which would need a massive*increase*of protein synthesis to “repair” the non-existent burn— hence the inclusion of the well-known TRPV agonist SV. We also have an angle here with upregulating IGF-1, which enhances TRPV1, which enhances IGF-1 signaling, which enhances TRPV1, ad nauseum and kick-starts a collaborative signaling cascade. In case you’re new to this, IGF-1 is kind of a big deal (14). And for the cherry on top, we have enhanced browning of adipose cells, making them more metabolically active and shifting them towards energy burning depots instead of energy storing (15), (16), (17), (18).
In summary, SV promotes muscle growth and repair through HSP/IGF-1 signaling, with a bonus effect of triggering browning of fat cells.
Ursolic Acid
Ursolic Acid earns a spot in the TopMuscle™ formula based on its ability to further target two of the previously mentioned pathways, as well as a third pathway that will be a common theme with some of the upcoming ingredients (so pay attention).
For starters, UA favorably triggers that sweet, sweet IGF-1 pathway (19), (20). Additionally, UA allows us to reduce the myostatin governor of muscle growth (21).
The third pathway involves something called irisin, which will be a recurring theme in this write up as we continue to unveil the formula. Irisin is a myokine triggered by exercise, which favorably modulates several pathways involving inhibition of fat gain, adipocyte browning, and muscle growth. In a study involving 16 healthy males, adding UA to a resistance training protocol for 8 weeks resulted in significantly decreased body fat percentage, elevated IGF-1 and irisin, as well as boosting strength levels (all vs. placebo pill combined with resistance training) (20).
In summary, combined research shows UA supports an increase in muscle fiber size, strength, exercise capacity, adipocyte browning, IGF-1, irisin, and protein synthesis. It also promotes a suppression of myostatin, inflammatory cytokines, and body fat accumulation (19), (20), (21).
Benzyl Nicotinate
Making up part of the Vitamin B3 complex, BN is included in the TopMuscle™ formula for its ability to trigger vasodilation as well as skin penetration enhancement (22), (23). As we all know, the ability to actually deliver nutrients to muscle is essential for growth.
Betulinic Acid
BA can be found in nature in several species of plant bark.
The inclusion of this ingredient is based on an interesting hypothesis that we will briefly explain to get you up to speed.
An enzyme called Ptp1b is a negative regulator of the insulin signaling pathway, and when we inhibit this enzyme, we augment something called VEGF (a protein that stimulates the formation of new blood vessels from pre-existing vasculature raw materials, a process called angiogenesis) (24), (25).
Some of you might be able to see where we’re going with this; plaque buildup in the vessels (particularly due to things getting gummed up with glucose malfunctions/carbohydrate intolerance) can lead to reduced blood flow to skeletal muscle as well as adipose tissue.
This is where we have a common “choke point” in muscle gain and fat loss; reduced blood flow and nutrient delivery creates a stalling out of both processes. By triggering angiogenesis through VEGF, we can hypothetically upregulate both muscle building and fat loss. Make sense?
Bringing the hypothesis into reality, research has demonstrated that blocking Ptp1b increases muscle glucose uptake, enhances glucose tolerance, and improves insulin sensitivity (26).
Now for the good stuff, let’s look at the actual research on BA. You knew this was coming, but BA has been shown to potently suppress Ptp1b (27). It also favorably modulates PPARy and PPARa, resulting in an inhibition of adipogenesis while triggering the osteogenesis pathway of differentiation (see BMP write-up for more info on why this is awesome) (28).
In rats induced with diabetes, BA significantly decreased serum insulin, inflammatory cytokines, and blood glucose (29). Speaking of blood glucose, this next aspect of BA is particularly interesting. Some people attempting low carb and/or ketogenic diets will find that even when their diet is dialed in for several weeks, they still have a high fasting blood glucose level. Once obvious adjustments are ruled out, this can often come down to excessive hepatic glucose production (your liver dumps glucose into the bloodstream, which keeps blood sugar elevated even when you’re consuming very low amounts of carbohydrates). BA has been shown to inhibit hepatic glucose production, which, in this study, translated to significantly reduced plasma glucose (-34%), as well as reduced triglycerides (-59%) (30). Look for the updated version of KetoInduce™ to include this angle.
In summary, BA suppresses Ptp1b, increases VEGF/angiogenesis, inhibits fat storage, triggers differentiation towards osteogenesis, inhibits hepatic glucose production, increases glucose uptake into muscle, and improves insulin sensitivity.
Arachidonic Acid
Quick prostaglandin primer - Arachidonic Acid is most abundant in the cellular membrane, most especially in muscle cells. Muscular injury causes the cellular membrane to slightly rupture, releasing Arachidonic Acid via Phospholipase A2, and triggering what is known as a prostaglandin cascade. These molecules not only cause inflammation and an immediate rapid healing response in that cell, but trigger adjoining cells to release their own prostaglandin reaction These cells propagate the signal to their adjoining cells, and so on. They are one of the primary signals of injury/healing in the body.
Arachidonic Acid is naturally occurring, found mainly in animal products. It is pro-inflammatory, which most people think of as a bad thing…don’t make that mistake. People tend to focus on anti-inflammation, but what we really want is inflammation resolution. Inflammation is a good thing; the body just needs to cycle through the process and resolve it. This is why chronic high dose fish oil is ill-advised, you’re just suppressing inflammation instead of encouraging the resolution cycle. This cycle is particularly important for muscle growth.
Aside from contributing to the inflammation resolution cycle, ArA has demonstrated several real-world benefits in current research. Using trained male subjects, researchers found that supplemental ArA, given over the course of 50 days and compared to placebo, enhanced peak and mean power output, while lowering IL-6 and elevating PGE2 (31).
ArA has been shown to increase expression of crucial muscle growth factors MyoD and myogenin, promoting myogenic gene expression in resistance trained men (32).
As ArA transits through the skin and into the muscle below, some of it will be converted to a metabolite known as 20-HETE. This metabolite does some important things. For one, it activates and sensitizes the TRPV1 receptor in humans, which, if you remember from the section on Stearoyl Vanillyamide, links with HSP activation (33). So not only do we have a second TRPV agonist, we are also sensitizing the receptors, allowing SV to be even more effective.
The 20-HETE metabolite has also been shown to increase angiogenesis through VEGF when muscles are induced with electrical stimulation (34). Fear not, there is no need to put a fork in an outlet. Electrical stimulation in this type of research is meant to mimic exercise, causing a perturbation, or cellular disturbance. We will explore this later in the write-up, but here’s two things to keep in mind: 1) Applying one of your TopMuscle™ doses pre-workout will provide additional benefits, and 2) We have included an ingredient called Escin which triggers this same exercise/cellular perturbation cascade, independent of working out.
In summary, ArA promotes inflammation resolution, myogenic gene expression, activates and sensitizes TRPV1 receptors, and boosts VEGF/angiogenesis.
PLCAR (Propionyl L-Carnitine)
PLCAR is a specific form of the amino acid carnitine. It finds its way into the TopMuscle™ formula for two main reasons, the first of which requires a quick dose of background science. Histone Deacetylase (HDAC) is an enzyme that has garnered significant attention in research recently, due to its inhibition being linked with anti-cancer benefits. For our purposes however, HDAC inhibition/inhibitors (HDACi’s) also aid muscle growth through multiple pathways.
For starters, carnitine is indeed an HDACi (35). In skeletal muscle and adipose, HDAC inhibition promotes PPARy and PGC-1a signaling, increased mitochondrial biogenesis, enhanced oxidative metabolism and energy expenditure, while reducing bodyweight, glucose and insulin (36).
And the really exciting news, HDAC inhibition has been shown to increase skeletal muscle size and reduce fat mass (37). This may be due, in part, to enhancing commitment of stem cells to the myocyte lineage (38).
Additionally, carnitine has been shown to upregulate androgen receptor density, giving testosterone more places to bind, and working handily with other ingredients in the formula (39).
In summary, PLCAR promotes muscle growth through HDAC inhibition and increasing androgen receptor density.
Escin
Escin is an active component of the more commonly known Horse Chestnut. Alluded to in the Arachidonic Acid section, Escin mimics cellular “injury” similar to exercise, by disrupting cell membranes (which will enhance the benefit/synergize with ArA and 20-HETE) (40). This will be enhanced by applying TopMuscle™ pre-workout yet will also provide a benefit to doses applied away from workouts.
Additionally, Escin also promotes muscle cell permeability and enhances microvasculature circulation, which acts as kind of a helper to other ingredients in the formula (41), (42).
Lastly, Escin triggers the release of the growth-promoting prostaglandin PGF2a from veins (43) and other cellular membranes that it contacts.
In summary, Escin enhances the effect of other ingredients while directly targeting growth through PGF2a. And through its permeabilizing effects, it also acts as its own penetration enhancer.
Ethyl Pyruvate
This one is short and sweet, Ethyl Pyruvate improves IGF-1 sensitivity as well as insulin sensitivity in muscle, unlike its salt counterpart (hence why Sodium Pyruvate supplementation turned out to be a huge zero). You will see this ingredient again from me, notably in the Slintensity™ update. (44), (45).
Matrine
HSP reminder - HSP 70/72 are triggered during exercise, notably from the action of muscle fibers sliding against each other (generating heat, of course). The HSPs are incredibly potent signaling molecules telling the body what it's doing and how it's interacting with the environment. Elevation of Heat Shock Proteins (notably HSP 70/72) indicate that the body is being physically taxed and that it will need to ramp up protein synthesis for repair.
An alkaloid from the Sophora Flavescens plant, Matrine promotes muscle growth through multiple pathways. By triggering PGE2 signaling, Matrine activates the EP2/EP4 pathway which regulates myogenesis by promoting myoblast proliferation (46), (47).
In addition, Matrine also throws its hat into the ring as another HSP activator (48).
To round things off, it also inhibits osteoclastogenesis and reduces some unwanted inflammatory cytokines (49).
Prunella Vulgaris/Rhizoma Anemarrhena Asphodeloides (Mangiferin)
GSK3a/b – A widely unknown pathway in the “muscle” world, GSK3a/b (also known as Glycogen Synthase Kinase 3a/b) is a crucial pathway for insulin/IGF-1/Protein Synthesis signaling. This one is a bit complex, so bear with me.
When IGF-1 binds to its receptor, a complicated cascade of anti-atrophic/anabolic processes occur. IGF-1 binding activates two immediate pathways – PI3K and Akt. Phosphorylation of Akt inhibits a protein called FOX0, a repressive protein that cripples MTORc2, and inhibits GSK3-b. GSK3-b inhibits protein synthesis via Nebulin and knocking out GSK3b not only amplifies insulin/IGF-1 anabolic signal, but directly “allows” for maximum muscle synthesis. GSK3b inhibition is one of the primary actions of IGF-1 hypertrophy.
We will also see an increase in b-catenin and PPARy. And for some bonus points, PV also promotes skin rejuvenation (50), (51), (52).
Andrographis Paniculata
TRPV4 primer - We've explained TRPV1 activation—a sensory receptor that tells the body when it has encountered heat levels that have "caused injury" requiring repair. With the SV we have simulated that injurious burn and triggered the healing response that can be harnessed for muscle growth. Well, the TRPV4 receptor also signals the state of our body—this time from stretching. TRPV4 receptors are highly expressed in the urogenital system (notably to signal when the bladder is full/has been stretched and must be evacuated). Well, muscle cells also express the TRPV4 receptors. When muscle cells are "stretched" to the point of causing micro-ruptures to the muscle fibers and cellular membranes, the TRPV4 receptor is activated. The Andrographolides in AP extract potently activate TRPV4.
AP is a plant native to Sri Lanka and India. First off, this ingredient joins forces with ArA and Escin to trigger “injury” sensing and propagating the muscle repair cascade. AP also promotes a huge increase in calcium efflux for promotion of strength gains (which we’ll touch on again later) (53), (54).
Like ArA and SV, Andrographis activates TRPV channels (TRPV4 specifically), which again translates to additional HSP benefits (55).
Additionally, AP has the unique ability to trigger stem cell activation through the Wnt/b-catenin pathway (56). And here’s why you should get excited about that: If we activate a stem cell, coupled with other ingredients in the formula that encourage myogenic differentiation pathways, we’re basically feeding the process in a continuous favorable loop.
5a-Hydroxy Laxogenin/Genistein
Laxogenin is functionally related to the ecdysteroid family, considered a brassinosteroid, with growth promoting activity (57). The exact mechanisms of why Ecdy/Laxogenin work are not clearly understood by most, and the answer might scare you at first. Be patient.
Estrogen Receptor Beta - I know what you're thinking. In the simplistic world of muscle, estrogen is BAD and must be minimized. Well, turns out the some highly aromatizable (easily converted to estrogens) compounds, like Dianabol, are often unmatched when it comes to building pure muscle mass. It turns out the estrogen signaling, via the ERb receptor, is critical for muscle satellite cell recruitment and expression of anabolic factors like MHC embryonic, MyoD, Pax7. ERb knockout animals have reduced hypertrophy, and stimulation of ERb via the ecdysterone family of compounds, as well as Genistein (an ERb specific agonist), causes an increase in muscle fiber size, IGF-1 expression, and hypertrophy. While systemic treatment with ERb agonists can have some negative effects on androgen receptor luciferase expression in male rat testes, it shows no such effects in skeletal muscle. The delivery system employed in TopMuscle™ keeps the ingredients localized.
Genistein was not only added to increase expression in ERb, it also functions to address an often overlooked player in the whole body process of protein turnover (and our desirable state of positive protein balance)—Annexin **. Annexin ** is highly involved in calcium signaling following exertion/injury (such as working out), as well as the recruitment of muscle satellite cells and recruitment of precursor cells to differentiate into new muscle. Annexin ** levels increase rapidly following membrane perturbation (see the Arachidonic Acid/Escin sections) as a potent repair signal, and can even cause/amplify these signals. Along with being a selective ERb agonist, Genistein also causes a rapid increase in Annexin ** levels.
In a rat study, brassinosteroids also significantly increased strength and muscle size, with no androgenic side effects (58). We may also see some more HSP activation through HSP23 (59).
Additionally, when combined with HDAC inhibitors, Laxogenin can demethylate histones to increase favorable gene transcription (60). Very briefly (as histone function is so highly complex that it fills many volumes alone), histones are proteins that control/guard DNA and either allow or prevent gene expression and protein synthesis. Histones generally have an acetyl head and a methyl tail that keeps it tightly wrapped around chromatin and prevents access to those genes. Extremely simplified in basic terms (so pedants might be frustrated, as actions can differ greatly), deacetylating histones causes them to wrap tighter. Histone deacetylase is the enzyme which accomplishes this. By preventing deacetylation, we can allow the histones to "open up" and allow for gene transcription and therefore, protein synthesis. The methyl tail, for our purposes of simplification, does the opposite. So for maximum access to allow for DNA/RNA interaction, the histones need to remain acetylated (via HDAC inhibition) while also slightly demethylated.
Ligustrazine
Also known as tetramethylpyrazine, this is a really interesting compound isolated from the fermented food natto.
First off, we’re going to circle back to the previously mentioned calcium angle. With regards to muscle growth and strength, calcium is your friend. So why not just take a calcium supplement? If only it were that easy. What we want to do, is promote calcium cycling, or efflux and influx—a similar concept to the “inflammation resolution” we covered earlier. So already we’ve got Andrographis promoting efflux…enter Ligustrazine. By upregulating the SERCA pump, it takes all of that released calcium and shoves it back into the sarcoplasmic reticulum, so it can be re-used (and eventually re-released, in a loop).
Next up, we’ve got a two-pronged attack from Ligustrazine—preventing muscle atrophy and promoting muscle growth. In research, there’s a few common ways to study muscle atrophy; one of them is to “denervate” a muscle, which involves clipping off the nerve supply, so it no longer gets electrical signals. I remember doing this in college biology lab, interesting stuff. You’re pretty much guaranteed a predictable amount of atrophy. Denervated rats treated with Ligustrazine lost significantly less muscle at 7, 14, and 28 days vs. control (61). Another common and reliable way to induce atrophy is to make a muscle weightless, which is referred to as “suspension”. The Ligustrazine treated rats showed significantly less muscle loss vs. control (62).
As for the second prong, Ligustrazine increases glucose uptake in muscle cells, upregulates mitochondrial biogenesis, and significantly increases BMP-7 (which is a key player in muscle growth, see BMP write-up for more info). And for a finishing move, it is a strong ROS scavenger, reduces unwanted inflammatory cytokines, and promotes vasodilation (63), (64).
Silibinin
Silibinin is a major component of Silymarin (milk thistle). The main target of Silibinin for our purposes is through upregulation of a protein called C/EBPb (65). This protein reduces apoptosis in stem cells and optimizes macrophage induced muscle healing. It also helps to optimize IGF-1 and insulin signaling, pairing nicely with the other TopMuscle™ ingredients targeting those pathways (66), (67).
Silibinin has also been shown to inhibit osteoclastogenesis, thereby favoring anabolic differentiation (68), (69).
Bupleurum Falcatum/Paeonia Suffruticosa/Angelica Dahurica
These three compounds all work together to inhibit something called Nuclear Receptor Related 1 Protein (NUUR1). The inhibition of NUUR1 increases skeletal muscle insulin sensitivity, and causes glycogen supercompensation in the muscle cell (70). Hopefully you don't need it explained why this is a highly anabolic state to be in, not to mention that it feels pretty cool to have that “always pumped” sensation.
Paeonia Veitchii Lynch
PVL is a species of the peony plant found in China. This compound brings several tricks to the table regarding muscle growth. Like Andrographis, PVL will promote calcium efflux, thereby working hand-in-hand with Lugustrazine to optimize calcium cycling (71).
In overfed mice, PVL has been shown to alleviate obese and insulin resistance, as well as increase glucose uptake in skeletal muscle (72).
PVL favorably modulates prostaglandin signaling, acting as an EP4 agonist, backing up ArA and Matrine on the job. It has also been shown to reduce joint pain, bone erosion, and cartilage degradation in arthritis (73).
Perhaps most intriguingly, PVL has been shown to induce skeletal muscle satellite cell recruitment (74).
Like Ligustrazine, PVL also supports BMP-7 expression (75).
Bakuchiol
Bakuchiol is a meroterpene structurally similar to resveratrol. This compound checks a bunch of boxes for us by reinforcing several previously targeted pathways towards muscle growth. Increased calcium efflux, enhanced myogenic differentiation through MyoD, osteoblast differentiation, vasodilation, BMP2 activation, as well as collagen upregulation in the skin (76), (77), (78), (79), (80), (81).
Methyl Butyrate, Methyl Valeric Acid
These are short chain fatty acids (SCFAs), and we can also include propionic acid from the PLCAR in the group. They have known HDACi properties, included solely for that purpose to take full advantage of that pathway (82).
Linalool
Linalool is a naturally occurring terpene alcohol found in numerous plants. To understand the benefits, we need to cover a quick conceptual background.
Skeletal muscle formation and growth require fusion of myoblasts to form myofibers or myotubes. A transcription factor called NFATc2 is a key player in controlling myoblast fusion after initial formation of a myotube, necessary for further cell growth. While NFATc2 is calcium activated, the cytokine IL-4 is the molecular signal (along with PGF2a) that controls myoblast fusion with pre-existing myotubes (83), (84), (85). Confusing stuff, but the upshot is that if we can juice up the IL-4 signaling in muscle cells, we can increase myoblast recruitment, and increase muscle growth. You guessed it, Linalool does just that (86), (87).
Linalool also contributes to TRPV4 activation, calcium increase, and vasodilation (88), (89).
Eucommia Ulmoides
EU comes from the bark of a small tree native to China, and has been thoroughly studied for a variety of effects on the brain and body.
Time to get old school here, we’re targeting androgens and GH. EU attaches to the androgen receptor, potentiating and optimizing androgenic effects. EU also induces the release of endogenous Growth Hormone (90).
EU also selectively increases GLUT-4 expression in skeletal muscles, improving insulin signaling and glucose uptake (91).
Lastly, EU will help us continue to hammer that BMP-2 angle of muscle growth (92).
Sesamol
A natural compound found in sesame seeds and sesame oil, Sesamol fires up several advantageous pathways. To briefly revisit and expand on Irisin (discussed in the Ursolic Acid section), exogenous Irisin has been shown to induce browning of white adipose cells, significantly increase IGF-1, decrease myostatin, upregulate PGC1a4 (a recently discovered isoform specifically related to skeletal muscle hypertrophy), inhibit lipid accumulation, decrease adipocyte differentiation, and downregulate GSK3b (discussed in the Prunella Vulgaris section) (93), (94).
Aside from triggering endogenous Irisin, Sesamol also provides several benefits through PPARa and PPARy agonism (95). First off, PPARa agonism increases Irisin sensitivity, thereby potentiating the effects (96). Additionally, PPARa agonism promotes beige cells in subcutaneous white adipose tissue (97). In a rat overfeeding study, Sesamol was able to decrease insulin resistance, hyperglycemia and dyslipidemia, while normalizing adiponectin and inflammatory markers vs. control (95).
You are now entering the realm of a product many years in development. The quest for physique enhancement fuels an entire industry, with false solutions offered en masse. The ability to target certain muscles for growth, whether due to musculoskeletal lag, or to help accelerate growth all over, is something that's been attempted a few times but always ending in disappointment.
For TopMuscle™, our researchers spent hundreds of hours exploring all of the growth signaling (anabolic) pathways that have been delineated. While the one that many people are familiar with, mTOR, is generally best tapped via dietary manipulation (through amino acids like leucine and its metabolites as we covered in our Strafe™ product), there are many more than can be triggered at a local level, resulting in optimization of muscle growth in a site-specific manner.
Ingredients and Function
Apigenin
Apigenin is a flavone found in a variety of fruits, vegetables and herbs, as well as wine, beer, chamomile tea, and Gingko biloba.
This flavone has been shown to promote skeletal muscle growth as well as myogenic differentiation (the process of converting a less specialized cell into a muscle cell). It does this through multiple pathways (the Prmt7-PGC1a-GPR56 pathway and the Prmt7-p38-MyoD pathway, for the nerds out there) (1).
In a 2017 study, overfed mice were given apigenin and compared to a control group without apigenin. The supplemented group had less fat accumulation, lower inflammatory cytokines, and increased levels of fat-free mass. They also showed reduced expression of muscle atrophy-promoting genes, as well as an increase in exercise capacity through upregulated mitochondrial function and biogenesis (2).
In summary, apigenin should promote muscle growth, muscle cell differentiation, reduced fat gain, and increased exercise capacity.
Alpha-Terpineol
Alpha-Terpineol is an alcohol, included in TopMuscle™ to help disrupt the lipid bilayer of the stratum corneum and epidermis (the outermost layers of the skin). This enhances penetration and delivery of certain ingredients topically, like epicatechin, and allows them to quicky penetrate into the underlying muscle without being picked up sytemically (3).
Gibberellic Acid
Gibberellic acid is an extremly potent hormone found in plants, responsible for promoting and regulating growth in those plants. For those of us who aren’t plants, we have good news. Gibberellic acid has also been shown to increase growth in animals, by enhancing the activity of a growth related enzyme called guanylate cyclase (4).
GA has also been shown to increase 3b-HSD and 17b-HSD enzymes for greater conversion of DHEA to testosterone, as well as Steroidogenic Acute Regulatory Protein (StAR) and Androgen Binding Protein (ABP). This results in elevated testosterone, which earned it a tag as being an “inducer of steroidogenesis” (5).
In summary, GA targets natural testosterone boosting, as well as non-hormonal routes of muscle growth.
Epicatechin
This ingredient has become quite popular in the past few years with regards to muscle growth, and for good reason. It appears to increase size and strength, and quickly. Strength increases have been documented in research after only seven days of use (6).
Epicatechin has been shown to decrease myostatin (and favorably modulate plasma follistatin:myostatin ratios), which is one of the main governors of muscle growth. It also increases skeletal muscle capillarity, increases mitochondrial biogenesis, and other markers of muscle growth (6), (7), (8), (9).
In summary, Epicatechin decreases myostatin, enhances muscle growth, and increases strength.
Stearoyl Vanillyamide
SV is a non-pungent analogue of capsaicin, which is the active component of chili peppers.
One purpose of including SV in our formula relates to Heat Shock Proteins, or HSPs.
Quick primer on HSPs (taken from our BMP 2.0 write-up):
When the body undergoes heat stress (like during exercise), the muscle cells have to control potential damage with HSPs. Often referred to as intracellular “chaperones”, they’re basically molecules that act as a clean-up crew to facilitate protein transport, prevent mishaps during protein folding, and protect against protein denaturation (10), (11), (12). They have also been shown to improve insulin sensitivity, reduce oxidative stress, inhibit inflammatory pathways, and enhance the metabolic characteristics of muscle cells (13).
Take home point, anything that increases specific HSPs will likely speed up recovery and muscle hypertrophy.
It turns out that TRPV channels are intricately and favorably linked with HSPs, in the sense that activating TRPV receptors initiates HSP activation (which makes sense since TRPV1 is activated in the presence of extreme heat levels such as when the body is being physically burned—which would need a massive*increase*of protein synthesis to “repair” the non-existent burn— hence the inclusion of the well-known TRPV agonist SV. We also have an angle here with upregulating IGF-1, which enhances TRPV1, which enhances IGF-1 signaling, which enhances TRPV1, ad nauseum and kick-starts a collaborative signaling cascade. In case you’re new to this, IGF-1 is kind of a big deal (14). And for the cherry on top, we have enhanced browning of adipose cells, making them more metabolically active and shifting them towards energy burning depots instead of energy storing (15), (16), (17), (18).
In summary, SV promotes muscle growth and repair through HSP/IGF-1 signaling, with a bonus effect of triggering browning of fat cells.
Ursolic Acid
Ursolic Acid earns a spot in the TopMuscle™ formula based on its ability to further target two of the previously mentioned pathways, as well as a third pathway that will be a common theme with some of the upcoming ingredients (so pay attention).
For starters, UA favorably triggers that sweet, sweet IGF-1 pathway (19), (20). Additionally, UA allows us to reduce the myostatin governor of muscle growth (21).
The third pathway involves something called irisin, which will be a recurring theme in this write up as we continue to unveil the formula. Irisin is a myokine triggered by exercise, which favorably modulates several pathways involving inhibition of fat gain, adipocyte browning, and muscle growth. In a study involving 16 healthy males, adding UA to a resistance training protocol for 8 weeks resulted in significantly decreased body fat percentage, elevated IGF-1 and irisin, as well as boosting strength levels (all vs. placebo pill combined with resistance training) (20).
In summary, combined research shows UA supports an increase in muscle fiber size, strength, exercise capacity, adipocyte browning, IGF-1, irisin, and protein synthesis. It also promotes a suppression of myostatin, inflammatory cytokines, and body fat accumulation (19), (20), (21).
Benzyl Nicotinate
Making up part of the Vitamin B3 complex, BN is included in the TopMuscle™ formula for its ability to trigger vasodilation as well as skin penetration enhancement (22), (23). As we all know, the ability to actually deliver nutrients to muscle is essential for growth.
Betulinic Acid
BA can be found in nature in several species of plant bark.
The inclusion of this ingredient is based on an interesting hypothesis that we will briefly explain to get you up to speed.
An enzyme called Ptp1b is a negative regulator of the insulin signaling pathway, and when we inhibit this enzyme, we augment something called VEGF (a protein that stimulates the formation of new blood vessels from pre-existing vasculature raw materials, a process called angiogenesis) (24), (25).
Some of you might be able to see where we’re going with this; plaque buildup in the vessels (particularly due to things getting gummed up with glucose malfunctions/carbohydrate intolerance) can lead to reduced blood flow to skeletal muscle as well as adipose tissue.
This is where we have a common “choke point” in muscle gain and fat loss; reduced blood flow and nutrient delivery creates a stalling out of both processes. By triggering angiogenesis through VEGF, we can hypothetically upregulate both muscle building and fat loss. Make sense?
Bringing the hypothesis into reality, research has demonstrated that blocking Ptp1b increases muscle glucose uptake, enhances glucose tolerance, and improves insulin sensitivity (26).
Now for the good stuff, let’s look at the actual research on BA. You knew this was coming, but BA has been shown to potently suppress Ptp1b (27). It also favorably modulates PPARy and PPARa, resulting in an inhibition of adipogenesis while triggering the osteogenesis pathway of differentiation (see BMP write-up for more info on why this is awesome) (28).
In rats induced with diabetes, BA significantly decreased serum insulin, inflammatory cytokines, and blood glucose (29). Speaking of blood glucose, this next aspect of BA is particularly interesting. Some people attempting low carb and/or ketogenic diets will find that even when their diet is dialed in for several weeks, they still have a high fasting blood glucose level. Once obvious adjustments are ruled out, this can often come down to excessive hepatic glucose production (your liver dumps glucose into the bloodstream, which keeps blood sugar elevated even when you’re consuming very low amounts of carbohydrates). BA has been shown to inhibit hepatic glucose production, which, in this study, translated to significantly reduced plasma glucose (-34%), as well as reduced triglycerides (-59%) (30). Look for the updated version of KetoInduce™ to include this angle.
In summary, BA suppresses Ptp1b, increases VEGF/angiogenesis, inhibits fat storage, triggers differentiation towards osteogenesis, inhibits hepatic glucose production, increases glucose uptake into muscle, and improves insulin sensitivity.
Arachidonic Acid
Quick prostaglandin primer - Arachidonic Acid is most abundant in the cellular membrane, most especially in muscle cells. Muscular injury causes the cellular membrane to slightly rupture, releasing Arachidonic Acid via Phospholipase A2, and triggering what is known as a prostaglandin cascade. These molecules not only cause inflammation and an immediate rapid healing response in that cell, but trigger adjoining cells to release their own prostaglandin reaction These cells propagate the signal to their adjoining cells, and so on. They are one of the primary signals of injury/healing in the body.
Arachidonic Acid is naturally occurring, found mainly in animal products. It is pro-inflammatory, which most people think of as a bad thing…don’t make that mistake. People tend to focus on anti-inflammation, but what we really want is inflammation resolution. Inflammation is a good thing; the body just needs to cycle through the process and resolve it. This is why chronic high dose fish oil is ill-advised, you’re just suppressing inflammation instead of encouraging the resolution cycle. This cycle is particularly important for muscle growth.
Aside from contributing to the inflammation resolution cycle, ArA has demonstrated several real-world benefits in current research. Using trained male subjects, researchers found that supplemental ArA, given over the course of 50 days and compared to placebo, enhanced peak and mean power output, while lowering IL-6 and elevating PGE2 (31).
ArA has been shown to increase expression of crucial muscle growth factors MyoD and myogenin, promoting myogenic gene expression in resistance trained men (32).
As ArA transits through the skin and into the muscle below, some of it will be converted to a metabolite known as 20-HETE. This metabolite does some important things. For one, it activates and sensitizes the TRPV1 receptor in humans, which, if you remember from the section on Stearoyl Vanillyamide, links with HSP activation (33). So not only do we have a second TRPV agonist, we are also sensitizing the receptors, allowing SV to be even more effective.
The 20-HETE metabolite has also been shown to increase angiogenesis through VEGF when muscles are induced with electrical stimulation (34). Fear not, there is no need to put a fork in an outlet. Electrical stimulation in this type of research is meant to mimic exercise, causing a perturbation, or cellular disturbance. We will explore this later in the write-up, but here’s two things to keep in mind: 1) Applying one of your TopMuscle™ doses pre-workout will provide additional benefits, and 2) We have included an ingredient called Escin which triggers this same exercise/cellular perturbation cascade, independent of working out.
In summary, ArA promotes inflammation resolution, myogenic gene expression, activates and sensitizes TRPV1 receptors, and boosts VEGF/angiogenesis.
PLCAR (Propionyl L-Carnitine)
PLCAR is a specific form of the amino acid carnitine. It finds its way into the TopMuscle™ formula for two main reasons, the first of which requires a quick dose of background science. Histone Deacetylase (HDAC) is an enzyme that has garnered significant attention in research recently, due to its inhibition being linked with anti-cancer benefits. For our purposes however, HDAC inhibition/inhibitors (HDACi’s) also aid muscle growth through multiple pathways.
For starters, carnitine is indeed an HDACi (35). In skeletal muscle and adipose, HDAC inhibition promotes PPARy and PGC-1a signaling, increased mitochondrial biogenesis, enhanced oxidative metabolism and energy expenditure, while reducing bodyweight, glucose and insulin (36).
And the really exciting news, HDAC inhibition has been shown to increase skeletal muscle size and reduce fat mass (37). This may be due, in part, to enhancing commitment of stem cells to the myocyte lineage (38).
Additionally, carnitine has been shown to upregulate androgen receptor density, giving testosterone more places to bind, and working handily with other ingredients in the formula (39).
In summary, PLCAR promotes muscle growth through HDAC inhibition and increasing androgen receptor density.
Escin
Escin is an active component of the more commonly known Horse Chestnut. Alluded to in the Arachidonic Acid section, Escin mimics cellular “injury” similar to exercise, by disrupting cell membranes (which will enhance the benefit/synergize with ArA and 20-HETE) (40). This will be enhanced by applying TopMuscle™ pre-workout yet will also provide a benefit to doses applied away from workouts.
Additionally, Escin also promotes muscle cell permeability and enhances microvasculature circulation, which acts as kind of a helper to other ingredients in the formula (41), (42).
Lastly, Escin triggers the release of the growth-promoting prostaglandin PGF2a from veins (43) and other cellular membranes that it contacts.
In summary, Escin enhances the effect of other ingredients while directly targeting growth through PGF2a. And through its permeabilizing effects, it also acts as its own penetration enhancer.
Ethyl Pyruvate
This one is short and sweet, Ethyl Pyruvate improves IGF-1 sensitivity as well as insulin sensitivity in muscle, unlike its salt counterpart (hence why Sodium Pyruvate supplementation turned out to be a huge zero). You will see this ingredient again from me, notably in the Slintensity™ update. (44), (45).
Matrine
HSP reminder - HSP 70/72 are triggered during exercise, notably from the action of muscle fibers sliding against each other (generating heat, of course). The HSPs are incredibly potent signaling molecules telling the body what it's doing and how it's interacting with the environment. Elevation of Heat Shock Proteins (notably HSP 70/72) indicate that the body is being physically taxed and that it will need to ramp up protein synthesis for repair.
An alkaloid from the Sophora Flavescens plant, Matrine promotes muscle growth through multiple pathways. By triggering PGE2 signaling, Matrine activates the EP2/EP4 pathway which regulates myogenesis by promoting myoblast proliferation (46), (47).
In addition, Matrine also throws its hat into the ring as another HSP activator (48).
To round things off, it also inhibits osteoclastogenesis and reduces some unwanted inflammatory cytokines (49).
Prunella Vulgaris/Rhizoma Anemarrhena Asphodeloides (Mangiferin)
GSK3a/b – A widely unknown pathway in the “muscle” world, GSK3a/b (also known as Glycogen Synthase Kinase 3a/b) is a crucial pathway for insulin/IGF-1/Protein Synthesis signaling. This one is a bit complex, so bear with me.
When IGF-1 binds to its receptor, a complicated cascade of anti-atrophic/anabolic processes occur. IGF-1 binding activates two immediate pathways – PI3K and Akt. Phosphorylation of Akt inhibits a protein called FOX0, a repressive protein that cripples MTORc2, and inhibits GSK3-b. GSK3-b inhibits protein synthesis via Nebulin and knocking out GSK3b not only amplifies insulin/IGF-1 anabolic signal, but directly “allows” for maximum muscle synthesis. GSK3b inhibition is one of the primary actions of IGF-1 hypertrophy.
We will also see an increase in b-catenin and PPARy. And for some bonus points, PV also promotes skin rejuvenation (50), (51), (52).
Andrographis Paniculata
TRPV4 primer - We've explained TRPV1 activation—a sensory receptor that tells the body when it has encountered heat levels that have "caused injury" requiring repair. With the SV we have simulated that injurious burn and triggered the healing response that can be harnessed for muscle growth. Well, the TRPV4 receptor also signals the state of our body—this time from stretching. TRPV4 receptors are highly expressed in the urogenital system (notably to signal when the bladder is full/has been stretched and must be evacuated). Well, muscle cells also express the TRPV4 receptors. When muscle cells are "stretched" to the point of causing micro-ruptures to the muscle fibers and cellular membranes, the TRPV4 receptor is activated. The Andrographolides in AP extract potently activate TRPV4.
AP is a plant native to Sri Lanka and India. First off, this ingredient joins forces with ArA and Escin to trigger “injury” sensing and propagating the muscle repair cascade. AP also promotes a huge increase in calcium efflux for promotion of strength gains (which we’ll touch on again later) (53), (54).
Like ArA and SV, Andrographis activates TRPV channels (TRPV4 specifically), which again translates to additional HSP benefits (55).
Additionally, AP has the unique ability to trigger stem cell activation through the Wnt/b-catenin pathway (56). And here’s why you should get excited about that: If we activate a stem cell, coupled with other ingredients in the formula that encourage myogenic differentiation pathways, we’re basically feeding the process in a continuous favorable loop.
5a-Hydroxy Laxogenin/Genistein
Laxogenin is functionally related to the ecdysteroid family, considered a brassinosteroid, with growth promoting activity (57). The exact mechanisms of why Ecdy/Laxogenin work are not clearly understood by most, and the answer might scare you at first. Be patient.
Estrogen Receptor Beta - I know what you're thinking. In the simplistic world of muscle, estrogen is BAD and must be minimized. Well, turns out the some highly aromatizable (easily converted to estrogens) compounds, like Dianabol, are often unmatched when it comes to building pure muscle mass. It turns out the estrogen signaling, via the ERb receptor, is critical for muscle satellite cell recruitment and expression of anabolic factors like MHC embryonic, MyoD, Pax7. ERb knockout animals have reduced hypertrophy, and stimulation of ERb via the ecdysterone family of compounds, as well as Genistein (an ERb specific agonist), causes an increase in muscle fiber size, IGF-1 expression, and hypertrophy. While systemic treatment with ERb agonists can have some negative effects on androgen receptor luciferase expression in male rat testes, it shows no such effects in skeletal muscle. The delivery system employed in TopMuscle™ keeps the ingredients localized.
Genistein was not only added to increase expression in ERb, it also functions to address an often overlooked player in the whole body process of protein turnover (and our desirable state of positive protein balance)—Annexin **. Annexin ** is highly involved in calcium signaling following exertion/injury (such as working out), as well as the recruitment of muscle satellite cells and recruitment of precursor cells to differentiate into new muscle. Annexin ** levels increase rapidly following membrane perturbation (see the Arachidonic Acid/Escin sections) as a potent repair signal, and can even cause/amplify these signals. Along with being a selective ERb agonist, Genistein also causes a rapid increase in Annexin ** levels.
In a rat study, brassinosteroids also significantly increased strength and muscle size, with no androgenic side effects (58). We may also see some more HSP activation through HSP23 (59).
Additionally, when combined with HDAC inhibitors, Laxogenin can demethylate histones to increase favorable gene transcription (60). Very briefly (as histone function is so highly complex that it fills many volumes alone), histones are proteins that control/guard DNA and either allow or prevent gene expression and protein synthesis. Histones generally have an acetyl head and a methyl tail that keeps it tightly wrapped around chromatin and prevents access to those genes. Extremely simplified in basic terms (so pedants might be frustrated, as actions can differ greatly), deacetylating histones causes them to wrap tighter. Histone deacetylase is the enzyme which accomplishes this. By preventing deacetylation, we can allow the histones to "open up" and allow for gene transcription and therefore, protein synthesis. The methyl tail, for our purposes of simplification, does the opposite. So for maximum access to allow for DNA/RNA interaction, the histones need to remain acetylated (via HDAC inhibition) while also slightly demethylated.
Ligustrazine
Also known as tetramethylpyrazine, this is a really interesting compound isolated from the fermented food natto.
First off, we’re going to circle back to the previously mentioned calcium angle. With regards to muscle growth and strength, calcium is your friend. So why not just take a calcium supplement? If only it were that easy. What we want to do, is promote calcium cycling, or efflux and influx—a similar concept to the “inflammation resolution” we covered earlier. So already we’ve got Andrographis promoting efflux…enter Ligustrazine. By upregulating the SERCA pump, it takes all of that released calcium and shoves it back into the sarcoplasmic reticulum, so it can be re-used (and eventually re-released, in a loop).
Next up, we’ve got a two-pronged attack from Ligustrazine—preventing muscle atrophy and promoting muscle growth. In research, there’s a few common ways to study muscle atrophy; one of them is to “denervate” a muscle, which involves clipping off the nerve supply, so it no longer gets electrical signals. I remember doing this in college biology lab, interesting stuff. You’re pretty much guaranteed a predictable amount of atrophy. Denervated rats treated with Ligustrazine lost significantly less muscle at 7, 14, and 28 days vs. control (61). Another common and reliable way to induce atrophy is to make a muscle weightless, which is referred to as “suspension”. The Ligustrazine treated rats showed significantly less muscle loss vs. control (62).
As for the second prong, Ligustrazine increases glucose uptake in muscle cells, upregulates mitochondrial biogenesis, and significantly increases BMP-7 (which is a key player in muscle growth, see BMP write-up for more info). And for a finishing move, it is a strong ROS scavenger, reduces unwanted inflammatory cytokines, and promotes vasodilation (63), (64).
Silibinin
Silibinin is a major component of Silymarin (milk thistle). The main target of Silibinin for our purposes is through upregulation of a protein called C/EBPb (65). This protein reduces apoptosis in stem cells and optimizes macrophage induced muscle healing. It also helps to optimize IGF-1 and insulin signaling, pairing nicely with the other TopMuscle™ ingredients targeting those pathways (66), (67).
Silibinin has also been shown to inhibit osteoclastogenesis, thereby favoring anabolic differentiation (68), (69).
Bupleurum Falcatum/Paeonia Suffruticosa/Angelica Dahurica
These three compounds all work together to inhibit something called Nuclear Receptor Related 1 Protein (NUUR1). The inhibition of NUUR1 increases skeletal muscle insulin sensitivity, and causes glycogen supercompensation in the muscle cell (70). Hopefully you don't need it explained why this is a highly anabolic state to be in, not to mention that it feels pretty cool to have that “always pumped” sensation.
Paeonia Veitchii Lynch
PVL is a species of the peony plant found in China. This compound brings several tricks to the table regarding muscle growth. Like Andrographis, PVL will promote calcium efflux, thereby working hand-in-hand with Lugustrazine to optimize calcium cycling (71).
In overfed mice, PVL has been shown to alleviate obese and insulin resistance, as well as increase glucose uptake in skeletal muscle (72).
PVL favorably modulates prostaglandin signaling, acting as an EP4 agonist, backing up ArA and Matrine on the job. It has also been shown to reduce joint pain, bone erosion, and cartilage degradation in arthritis (73).
Perhaps most intriguingly, PVL has been shown to induce skeletal muscle satellite cell recruitment (74).
Like Ligustrazine, PVL also supports BMP-7 expression (75).
Bakuchiol
Bakuchiol is a meroterpene structurally similar to resveratrol. This compound checks a bunch of boxes for us by reinforcing several previously targeted pathways towards muscle growth. Increased calcium efflux, enhanced myogenic differentiation through MyoD, osteoblast differentiation, vasodilation, BMP2 activation, as well as collagen upregulation in the skin (76), (77), (78), (79), (80), (81).
Methyl Butyrate, Methyl Valeric Acid
These are short chain fatty acids (SCFAs), and we can also include propionic acid from the PLCAR in the group. They have known HDACi properties, included solely for that purpose to take full advantage of that pathway (82).
Linalool
Linalool is a naturally occurring terpene alcohol found in numerous plants. To understand the benefits, we need to cover a quick conceptual background.
Skeletal muscle formation and growth require fusion of myoblasts to form myofibers or myotubes. A transcription factor called NFATc2 is a key player in controlling myoblast fusion after initial formation of a myotube, necessary for further cell growth. While NFATc2 is calcium activated, the cytokine IL-4 is the molecular signal (along with PGF2a) that controls myoblast fusion with pre-existing myotubes (83), (84), (85). Confusing stuff, but the upshot is that if we can juice up the IL-4 signaling in muscle cells, we can increase myoblast recruitment, and increase muscle growth. You guessed it, Linalool does just that (86), (87).
Linalool also contributes to TRPV4 activation, calcium increase, and vasodilation (88), (89).
Eucommia Ulmoides
EU comes from the bark of a small tree native to China, and has been thoroughly studied for a variety of effects on the brain and body.
Time to get old school here, we’re targeting androgens and GH. EU attaches to the androgen receptor, potentiating and optimizing androgenic effects. EU also induces the release of endogenous Growth Hormone (90).
EU also selectively increases GLUT-4 expression in skeletal muscles, improving insulin signaling and glucose uptake (91).
Lastly, EU will help us continue to hammer that BMP-2 angle of muscle growth (92).
Sesamol
A natural compound found in sesame seeds and sesame oil, Sesamol fires up several advantageous pathways. To briefly revisit and expand on Irisin (discussed in the Ursolic Acid section), exogenous Irisin has been shown to induce browning of white adipose cells, significantly increase IGF-1, decrease myostatin, upregulate PGC1a4 (a recently discovered isoform specifically related to skeletal muscle hypertrophy), inhibit lipid accumulation, decrease adipocyte differentiation, and downregulate GSK3b (discussed in the Prunella Vulgaris section) (93), (94).
Aside from triggering endogenous Irisin, Sesamol also provides several benefits through PPARa and PPARy agonism (95). First off, PPARa agonism increases Irisin sensitivity, thereby potentiating the effects (96). Additionally, PPARa agonism promotes beige cells in subcutaneous white adipose tissue (97). In a rat overfeeding study, Sesamol was able to decrease insulin resistance, hyperglycemia and dyslipidemia, while normalizing adiponectin and inflammatory markers vs. control (95).
