This was a long process to refine to the point of making it easy to understand. The mechanisms aren't hugely difficult, and came from a hypothesis that Bone is one of the primary control organs of phenotype expression - whether weak bones, low muscle mass, and higher fat or lean, mean and ready to rumble.
The longer research goes on, and the more we understand, it becomes clear that the human body is always in a state of dynamic crosstalk and metabolic interplay. It's not ideal to simply hit one pathway strong and expect the best results possible. We're zeroing in on the master control switches of phenotype expression, and this is good news for those of us that strive to be our best. Now, without any more of my rambling or overexplanation, here we are:
BMP Write-up
Intro
We are extremely excited to open the door to a new frontier in anabolic supplementation. The pathway targeted in this formula doesn’t involve any of the well-known traditional methods, and will require no PCT or additional supplements to counteract side effects, because there aren’t any. Once user feedback gets around, you will certainly start seeing copycat formulas, as the concept of this formula has huge potential to accelerate muscle growth.
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 research has 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 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.
Definitions
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
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
BMP4, while still important, is 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
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
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.
Chondrocyte
This is just a cartilage cell. That was easy.
Chondrogenesis
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.
Osteoblast
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.
Osteoclast
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
Proliferation is simply the increase in cell number through the process of cell division.
Differentiation
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 Cyclodextrin
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 possible “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
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).
Osthole Cyclodextrin
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).
Tocopherols (Mixed)
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.
The longer research goes on, and the more we understand, it becomes clear that the human body is always in a state of dynamic crosstalk and metabolic interplay. It's not ideal to simply hit one pathway strong and expect the best results possible. We're zeroing in on the master control switches of phenotype expression, and this is good news for those of us that strive to be our best. Now, without any more of my rambling or overexplanation, here we are:
BMP Write-up
Intro
We are extremely excited to open the door to a new frontier in anabolic supplementation. The pathway targeted in this formula doesn’t involve any of the well-known traditional methods, and will require no PCT or additional supplements to counteract side effects, because there aren’t any. Once user feedback gets around, you will certainly start seeing copycat formulas, as the concept of this formula has huge potential to accelerate muscle growth.
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 research has 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 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.
Definitions
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
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
BMP4, while still important, is 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
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
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.
Chondrocyte
This is just a cartilage cell. That was easy.
Chondrogenesis
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.
Osteoblast
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.
Osteoclast
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
Proliferation is simply the increase in cell number through the process of cell division.
Differentiation
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 Cyclodextrin
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 possible “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
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).
Osthole Cyclodextrin
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).
Tocopherols (Mixed)
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.