EvoMuse released the original BMP formula almost a year ago and it became extremely popular with tons of great user feedback, fully delivering on the muscle building hype. During this time however, we’ve found a way to make BMP even better while still keeping it just as cost-effective. If you’re familiar with the original formula, you’ll notice quite a few similarities, but also a few key changes that we’re confident will give users even better results.
BMP, for the sake of our new groundbreaking formula, stands for Body Modify- Phenotype.
For the sake of the physiology it happens to be targeting, it stands for Bone Morphogenetic Protein.
Based on new research, it turns out that a pathway once thought to only regulate bone growth/turnover is actually tightly and crucially linked to muscle growth as well. Since this research began to surface, we’ve been watching it like a hawk and researching ingredients that might take advantage of this pathway. Now that more and more data have confirmed the previous conclusions, we are confident that EvoMuse BMP is about to dig its heels in as a serious player in the toolbox for natural and assisted bodybuilders.
Much of the research we have access to at this point is looking at bone anabolism as opposed to muscle, as the BMP-muscle link is such a new area. So we will have to extrapolate a bit and look at implications of the ingredients’ effects on bone growth through BMP, knowing that the same pathway is going to target muscle growth as well. At this point, when we find something that targets bone growth through supporting the BMP pathway, we can assume increased rates of muscle growth will accompany.
Since this is quite a dense topic, it will be exponentially easier to understand, and flow through reading the write-up if several terms/concepts are at least superficially understood. Scan through these definitions first, and then refer back to them as you go through the write-up as you need clarification.
Bone Morphogenetic Proteins (BMPs)
BMPs are a class of growth factors belonging to the Transforming Growth Factor beta (TGF-b) superfamily. Another, contrasting part of this superfamily is the myostatin/activin subfamily.
These two subfamilies have directly opposing functions on muscle mass, namely that BMPs are anabolic and myostatin is catabolic. Originally it was thought that BMPs were responsible, solely, for bone and cartilage formation, but recently it has been discovered that they are also key players in skeletal muscle growth.
Interestingly, BMPs are actually dominant over myostatin signaling; when levels are high they win the anabolic/catabolic battle. BMPs are divided into specific proteins, namely BMP2, BMP4, and BMP7.
BMP’s promote chondrocyte proliferation AND hypertrophy, and SMAD signaling (see below) regulates chondrocyte hypertrophy (1). BMP’s are unique in that they not only induce differentiation of mesenchymal stem cells to osteoblasts, and they also enhance the function of the osteoblast once differentiated (2).
A 2013 study published in the journal Nature Genetics provided some compelling conclusions about BMP and muscle tissue (3).
-BMP signaling is the fundamental signal for hypertrophy.
-Inhibiting BMP signaling causes atrophy, abolishes myostatin deficient mice from gaining the enormous amount of muscle they normally do, and increases the negative effect from fasting.
-BMP plays a critical role in adult muscle growth.
Now we’ll take a look at the specific types of BMPs.
BMP2 plays a major role in bone and cartilage formation, as well as osteoblast differentiation. Differentiation is an important point here, as will be discussed below. BMP2 is the secondary target of this formula, with BMP7 being the primary target.
BMP4, while still important, is comparatively our lowest priority of the three for targeting muscle growth. Like the other BMPs it is involved in bone and cartilage development, although more specifically for teeth and limbs, as well as being a key player during embryonic development.
BMP7 is our priority target for muscle growth. It is a major player in osteoblast differentiation as well as the induction of SMAD1 and SMAD5 (see below).
SMADs are a family of nine proteins that live inside the cell, which fall into one of three categories (receptor-regulated, common-mediator, or inhibitory). The first two classes help to mediate BMP by bringing the extracellular signal into the nucleus of the cell where they trigger gene transcription downstream.
SMAD4, which makes up the entirety of the common-mediator class, is a helper protein for SMAD1/2/3/5/8/9, which make up the receptor-regulated class. Once BMPs hit the cell membrane, this triggers the phosphorylation of SMAD1/5/8; they then form a complex with SMAD4 and are translocated to the nucleus. SMADs basically act as an executive assistant to BMPs.
This is just a cartilage cell. That was easy.
The formation of cartilage. Another gimmie.
Mesenchymal Stem Cell (MSC)
MSC’s are stem cells located in connective tissue throughout the body, which can differentiate down different pathways into chondrocytes, osteoblasts, or adipocytes.
Formed from MSC’s, these cells, once grouped together are responsible for synthesizing bone. Since bone is a dynamic tissue, these cells are constantly working in anabolic opposition to the catabolic osteoclasts.
A catabolic bone cell, osteoclasts oppose osteoblasts and encourage bone resorption (the process of breaking down bones which pushes calcium into the blood).
Wnt Signaling Pathways
These pathways are made up of proteins that function in a way similar to SMADs, helping pass signals from outside to inside a cell, as well as regulating b-catenin from the cytoplasm to the nucleus. This pathway is also responsible for regulating calcium inside the cell, as well as aiding in differentiation and proliferation.
Notch Signaling Pathway
This pathway involves cell to cell communication; for example when one cell expresses a specific trait, this pathway can be used to switch that trait off in a neighboring cell to allow a process of many cells gathering together to form large structures. It is also upstream of several differentiation processes, and encourages the osteoblast pathway from stem cells (4).
Proliferation is simply the increase in cell number through the process of cell division.
This is the process where a non-specific stem cell becomes a specific type of cell, like an osteoblast.
Feel smarter? Good. Time to break down the ingredients in the formula and see what this stuff is all about.
Kaempferol is a flavonol found in a variety of plants. The Cyclodextrin has been added to increase bioavailability. In the past Kaempferol has been shown to increase cellular energy expenditure and enhance thyroid function which has landed it a spot in several fat burning formulas, however it has been included in this formula for an entirely different reason (5).
Kaempferol appears to have quite a strong effect on bone anabolism, and has been called a "promising agent for the prevention or treatment of bone loss” (6). A 2013 in vitro study demonstrated that Kaempferol enhanced the expression of chondrogenic marker genes, and greatly increased expression of BMP2 (7). In addition to increasing BMP2, it has also been shown to increase the number of BMP2 receptors in animals (8). More BMP and more places to dock, that’s a solid combo.
Through a complex signaling cascade involving TAZ, RUNX2, and PPARy, MSC’s differentiate into osteoblasts or adipose tissue. Kaempferol facilitates the ability of TAZ and RUNX2 to suppress gene transcription of PPARy targets (9). Yeah, that’s confusing. So what that means to us, is that Kaempferol causes those undifferentiated MSC’s to shift to bone cells instead of fat cells. Which is pretty cool.
Finally, Kaempferol has been shown to have a significant inhibitory effect on bone resorption, shifting the pendulum in favor of bone anabolism (10). It is worth noting, that at least part of this effect is attributable to bone specific estrogenic activity from Kaempferol which is the mechanism in which drugs like tamoxifen and toremifene help increase bone density.
Salidroside is an extremely interesting glucoside found in Rhodiola Rosea, which boasts numerous studies demonstrating a wide range of health benefits. Two very recent studies looked at the effect of Salidroside on bone anabolism. In the first study, they found that Salidroside increased the mRNA level of genes controlling the BMP pathway. It elevated BMP2 and BMP7 as well as SMAD1/5/8 (SMAD6/7 are the inhibitory ones we don’t want to activate) (11).
The second study, carried out by different researchers, confirmed the increased phosphorylation and expression of SMAD1/5/8. Then to be sure this was mediated by BMP, they added in a BMP antagonist to block the signaling pathway. As suspected, this attenuated the effect, demonstrating that BMP was indeed the target of Salidroside (12).
For the new BMP formula, you might have noticed that we slightly reduced the dosage of Salidroside over the old version, finding that we can still get the same benefit with a lower dose and therefore allowing the addition of new ingredients while still making the formula just as cost-effective for the user.
Found in cnidium monnieri and a few other plants, Osthole is classified as a coumarin. It has been used in supplement form for liver health, cognitive enhancement and vasodilation. Research shows it can activate AMPK and ACC, regulate blood glucose and GLUT4 activity, and decrease liver fat (13–15). One study even demonstrated that in mice, a high dose of Osthole had an androgenic effect and boosted LH and testosterone levels (16).
All these things are nice, but what about BMP? Fear not, Osthole has been shown to activate Wnt/beta-catenin signaling, increase BMP2 expression, and stimulate MSC differentiation to osteoblasts (17). Early phase differentiation involves BMP2, SMAD1/5/8, RUNX2, and p38, whereas later phase differentiation involves ERK1/2. Osthole has been shown to enhance both phases, it sticks around until the job is done (18,19).
Vitamin E is a fat soluble vitamin made up of four tocotrienols and four tocopherols, all with different functions. We have selected mixed tocopherols for this formula based on their potential benefits for BMP signaling.
In certain conditions where BMP7 is reduced, Vitamin E has been shown to prevent this (20). However, supplementation with normal synthetic Vitamin E will increase alpha tocopherol while lowering gamma tocopherol in the blood. High gamma:alpha ratios are associated with increased biomarkers of bone formation. The mixed tocopherols in the formula will help tip the balance in favor of Gamma Tocopherol over a traditional Vitamin E supplement. Gamma tocopherol demonstrates the ability to facilitate uncoupling of bone turnover, encouraging more bone formation than resorption (21). We know when this is happening, that the BMPs are working in our favor. If you typically take a synthetic Vitamin E supplement, you may want to consider shelving that while you’re taking BMP.
Alfacalcidol can be considered sort of a "super” Vitamin D3. Research has shown that elevated levels of Vitamin D3 plus BMP4/6 has a potent bone inducing effect (22). Typically during high stress, one of the things that gets left behind as the body redirects its resources, is optimal bone turnover. In rats treated with glucocorticoids to mimic stress, alfacalcidol preserved bone mineral density, strength, muscle volume, and prevented fatigue vs. controls (23). Research has also shown that alfacalcidol, but not regular Vitamin D, has pleiotropic effects (producing multiple actions from a single gene) improving bone and muscle metabolism (24).
Retinoic Acid (RA) is a Vitamin A metabolite, which aids the functions of Vitamin A necessary for growth and development. Due to the preferred differentiation of MSC’s to adipocytes in obesity, overweight or obese people are at a higher risk for osteoporosis due to less MSC’s converting to osteoblasts. RA has been shown to activate BMP & SMAD signaling, thereby shifting the direction of MSC’s to the osteoblast pathway (25). Interestingly, an increase in BMP2 stimulates MSC proliferation, but not always towards the osteoblast pathway. The addition of RA to elevated BMP2 seems to cooperate with BMP2 to further enhance proliferation, yet inhibits conversion of MSC’s to adipocytes, promoting early osteoblastic differentiation (26). Another study showed that RA was also synergistic with BMP9 in promoting the osteoblastic pathway (27). RA has also been shown to directly upregulate BMP7 activity (28).
Ligustrum Wallichii Extract (55% ligustrazine)
Isolated from the fermented food Natto, LWE is an interesting compound with well known anti-inflammatory and nootropic properties (29,30). More importantly, however, LWE has recently been shown to significantly elevate BMP7 (30). LWE also favorably works the anabolic bone and muscle signaling pathway by activating something called the SERCA pump, which brings extracellular calcium back into the cell so it can be re-used (31).
To determine the anabolic and/or anti-catabolic ability of a compound, scientists will often use methods such as denervation (cutting off or inhibiting nerve supply to a muscle), or suspension of a muscle (making it weightless). These methods basically make the brain forget these muscles exist, so they tend to atrophy quite rapidly. In multiple studies, when comparing Ligustrazine supplementation to control groups, in which both groups had been subjected to either denervation or muscle suspension, the Ligustrazine groups lost significantly less muscle over controls, both short term (one week) and longer term (one month) (32,33).
Ligustrazine has also been shown to selectively increase glucose uptake in muscle cells, protect against oxidative damage from high fat and high glucose, block vasoconstriction, and even upregulate mitochondrial biogenesis (30,34).
Paeoniflorin is a compound isolated from a fresh water fern by the name of Salvinia molesta. Working through multiple mechanisms, Paeoniflorin has a direct stimulatory effect on bone formation signaling (35). The current research on this compound has looked mainly at the potential beneficial effects in certain bone related disease states, which we can use to make some reasonable assumptions in how it might behave in healthy individuals. Renal fibrosis involves the accumulation of excess fibrous material in the extracellular matrix of kidney cells,
Renal (kidney) fibrosis is the principal process underlying the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). In this condition, BMP-7 expression and SMAD activation tends to become quite disrupted, and Paeoniflorin has been shown to normalize this signaling (36). This could very well translate to increased BMP-7 expression in healthy individuals.
In Rheumatoid Arthritis (RA), the body attacks the joints through an inflammatory cascade, causing pain, joint swelling, bone erosion and cartilage breakdown. Paeoniflorin supplementation has been shown to reverse or severely diminish all of these problems, largely through controlling the inflammatory factors prostaglandin E2, leukotriene B4, ROS, and cytokines IL-1B and TNF-a (37,38).
Again with regard to disease state models, we have some data regarding the effect of Paeoniflorin on periodontitis, which is an inflammatory condition that causes shrinking of the gums and bone loss in the teeth. In periodontic subjects supplementing with Paeoniflorin, alveolar bone loss and soft tissue destruction were significantly prevented and the compound exhibited anti-inflammatory and immunoregulatory effects (39).
Finally, as a bonus point, we’ve got a cool interaction with Heat Shock Proteins (HSPs). 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 (40–42). They have also been shown to improve insulin sensitivity, reduce oxidative stress, inhibit inflammatory pathways and enhance the metabolic characteristics of muscle cells (43).
Anything that increases specific HSPs will likely speed up recovery and hypertrophy, and as you may have guessed by now, Paeoniflorin does just that. Scientists looked at the effect of Glycyrrhizin (the active component of licorice) and Paeoniflorin on HSPs. They found that Paeoniflorin was able to induce HSP expression and also enhance the function of the elevated HSPs, whereas Glycyrrhizin was only able to enhance their function (44).
Sorghum Extract (SE)
Sorghum refers to a genus of grasses, typically used in livestock feed. As you can probably assume by now, we didn’t just throw some grass clippings in this advanced formula. We have found a very specific extract of Sorghum that boasts some cool properties. SE works, for our purposes, in a unique way that should synergize with the other ingredients in the formula.
Growth Hormone (GH) is a well-known regulator of bone growth. When GH is elevated, it triggers something called the Jak/STAT pathway, which regulates IGF-1, a major player in bone and muscle growth. HSE has been shown to act almost exactly like GH in activating this Jak/STAT pathway, which then increases the expression of GH related proteins, (one of which, STAT5b, triggers BMP7), the GH receptor itself, IGF-1, the IGF-1 receptor, and BMP7 (45). The science nerds might have noticed something particularly intriguing about that. When we trigger more BMP7, we trigger more MSC differentiation towards osteoblasts, giving the (now also elevated by HSE) anabolic IGF-1 more beneficial places to exert its effects.
And for the bonus round, SE has been shown to reduce plasma Total Cholesterol and Triglycerides when given to obese rats on a high fat diet (46).
For the new BMP formula we have increased the dose from 125mg up to 200mg to get even more of a boost from this powerful compound.
Things to Avoid/Monitor When Taking BMP
-Synthetic Vitamin E
The synthetic form of Vitamin E (dl-alpha tocopherol) lowers gamma tocopherol, which potentially interferes with anabolic bone signaling. If you are taking Vitamin E for a medical reason, please consult with your doctor before cessation.
Nicotine has been shown to interfere with bone formation. The addition of mixed tocopherols to the BMP formula could help counteract this, but it would still be a good idea to limit use of nicotine while using this product to prevent negative interactions with the BMP signaling cascade.
Things to stack with BMP
While certainly not necessary, these should provide a synergistic effect. For more information on the specifics, see the post on Anabolic Minds here.
-Any anabolic/androgenic steroid or prohormone that you’re currently taking
As you can see, we have found a highly specific combination of ingredients to optimize this exciting, untapped pathway for muscle growth. In consistent EvoMuse fashion, we have spared no cost ensuring optimal dosing of each ingredient for maximum effect. If you’re working out hard and eating right, you owe it to yourself to include EvoMuse BMP in your arsenal.
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