Here is an article from the July 2011 issue of MD:
Originally Posted by MD July 2011
Have Scientists Finally Discovered a Bona-Fide Natural Anabolic?
Scientific journal articles are released all the time that purportedly show amazing things from natural compounds. I have to break the news to you - most of them are bull****. Research is full of poorly designed studies, poorly carried out studies, and even outright fraud. It’s not that hard to weed out the ones which have a good possibility of being legitimate and which ones probably aren’t worth much attention. You can look at the study design - does it thoroughly take all variables into account? And what about the authors and the sponsors of the study – might there be a possibility of conflict of interest that may make you question the integrity of the author’s motives? And where is it published? Is it published in a major journal that has a high impact factor (a figure used to gauge the quality of a journal that is measured by accounting for the number of times articles are cited in other publications)?
I bring to you in this month’s column an article(Cell Metab. 2011 Jun 8;13(6):627-38.) that I find to be one of the most exciting pieces of research in the area of muscle building and natural products that I have seen in a long time – if ever. It comes from a journal called Cell Metabolism, which has a very impressive impact factor of 18.207. The thoroughness of the study and the obvious non-biased nature of the findings definitely caught my eye. The study examines a natural compound called Ursolic Acid which is found in many plants and foods such as apple peels (where it apparently is particularly abundant). This research impressed me so much that I decided to rush the ingredient to market through my brand E-Pharm, and by the time you read this it should be on the shelf under the name Ursobolic (and surely other companies will be releasing their versions as well).
So I am going to attempt to discuss this article and translate the hard science into layman’s terms the best I can. I hope you find it as interesting and impressive as I do.
Ursolic Acid and Muscle Atrophy
Skeletal muscle is a dynamic tissue that can undergo rapid growth (hypertrophy) or rapid shrinkage (atrophy) depending on the physiological conditions present in an animal or human. Situations where atrophy can prevail include starvation, nerve injury (i.e. spinal cord), diseases such as AIDS or cancer, and organ failure (heart, liver, kidney etc). To the contrary, muscle growth prevails during developmental stages and in response to stimuli such as exercise and certain drugs. These two phenomena – hypertrophy and atrophy – are driven by a multitude of genes which become expressed (or repressed) in response to any one of the aforementioned physiological triggers.
The scientists that performed the study I am discussing decided to exploit these genes in a screening study to investigate small molecules which may have effects on muscle wasting. They began by mapping mRNA expression signatures in muscle of people subjected to atrophy producing stress. Basically what this means is they starved a group of people, took biopsies of their muscles, and examined which muscle genes got activated and which got repressed. They detected hundreds of changes in mRNA expression in response to the fasting, and while most of these have physiological roles that have yet to be determined some of them of them encode proteins with known functions in muscle metabolism such as
Catabolic mRNAs (increased) – fat oxidation, protein synthesis inhibition, glutamine transport, ubiquitin mediated proteolysis
Anabolic mRNAs (decreased) - glycogen synthesis, polyamine synthesis, angiogenesis, mitochondrial biogenesis
Armed with this valuable data on muscle genes the researchers then turned to an interesting technique of screening bioactive molecules that uses a tool called “connectivity maps”. These connectivity maps utilize a vast database on over 1300 small compounds and their effects on gene expression on cells under various conditions. The map uses algorithms that allow researchers to screen for compounds that affect any mRNA expression signatures of interest they may have. In the case of the researchers in the study under discussion, the vast gene expression data initially collected was first reconciled with similar data on mouse muscle atrophy (the connectivity map utilizes mouse data), and then after the connectivity map magic was done two compounds stood out – Metformin and Ursolic Acid.
At this point they decided it was time to “prove the pudding” so to speak, so they administered metformin and ursolic acid to mice and then starved them for a day. They found that the control mice lost 9% of their muscle weight. Administration of Metformin had no effect on this. Ursolic acid treatment however dramatically reduced the muscle loss so that a net loss of only 2% of muscle weight was observed (and I would imagine some of this is due to water loss).
Since the fasting model of muscle atrophy successfully singled out Ursolic Acid as a strongly preventative bioactive molecule the researchers decided to examine another the model of muscle denervation, which was represented by the induction of spinal cord injury on some unfortunate mice. The mRNA signatures from this model of atrophy had some overlap with those seen in the fasting model, however there were substantial differences. And when the author’s queried the connectivity map they found once again that Ursolic Acid came out as a top candidate. Most interesting however was the fact that Ursolic Acid was the only compound identified by both the fasting and the muscle denervation search strategies.
At this point of course it was time to once again turn to in-vivo experimentation for some real world validation, and just as in the case of the fasting model they found Ursolic Acid passed the test. The sciatic nerves in the left hindlimb muscles of mice were dissected, and after a period of time these muscles were compared to the contralateral un-dissected right hindlimb muscles. Control mice exhibited a marked atrophy of the dissected muscle in relation to the un-dissected muscle, but when Ursolic Acid was administered this atrophy was greatly diminished.
Ursolic Acid and Muscle Hypertrophy
A compound that can prevent muscle loss in conditions of wasting is of enormous medical value and these researchers discovered one that has the ability to do so within the physiological environments of two somewhat disparate pathological conditions. Some readers of this magazine may find this very interesting but muscle building is obviously where their real fascination lies, and preventing muscle loss in catabolic states is quite a different animal that building more mass in healthy living creatures. Lucky for us these researchers tested Ursolic Acid in intact healthy mice. They simply fed the mice the compound in varying concentrations and after a period of five weeks they sacrificed them and compared their dissected muscles to control mice. Indeed, Ursolic Acid clearly had anabolic effects. The muscles were bigger (up to around 15% bigger) as were the muscle fibers themselves - which represents hypertrophy. But not only were the muscles bigger - measurements of grip strength showed they were stronger as well. That wasn’t the only interesting thing though.
Ursolic Acid and Fat loss
You figured that if these mice ingesting ursolic acid got such bigger muscles they probably gained weight. Such was not the case. To investigate this further the researches repeated the experiment but this time they fed the Ursolic Acid for 7 weeks instead of 5 weeks. Examination of muscle showed similar anabolic effects to the first time but when they looked at fat tissue they noticed dramatic mass reductions. In fact the reductions in fat mass were pretty much proportional to the gains in muscle mass. Such an inverse response of tissues is indication of a classical “repartitioning effect”. No differences in food intake were seen between Ursolic Acid mice and control mice, and examination of adipocytes (fat cells) revealed a marked reduction in size. Additionally, plasma cholesterol and triglycerides were reduced in Ursolic Acid treated mice.
How Does Ursolic Acid Work?
Ursolic Acid causes muscles to grow in healthy animals and minimizes muscle wasting in compromised animals - but how? The researchers tackled this question by once again examining mRNA levels in muscle (basically looking at which genes got turned on and which got turned off). Out of more than 16,000 mRNAs analyzed they found strong signals for 18mRNAs being decreased and 51 mRNAs being increased. Amongst the ones that were most potently decreased were two that are strongly associated with muscle atrophy – atrogin-1 and MuRF-1. On the other hand, one of the most highly upregulated mRNAs was for the one that encodes Insulin Growth Factor-1 (IGF-1). Autocrine (locally) produced muscular IGF-1 as you may know is considered one of the key signals in muscle growth and regeneration. Ursolic Acid was also shown to enhance the downstream effects of IGF-1, demonstrated by measurements of increased levels of Akt phosphorylation.
Will Ursolic Acid Work For Bodybuilders?
This is the key question isn’t it? Unfortunately I don’t have a definitive answer at the time I am writing this article. The research on it (which actually goes beyond what I have presented here) is so impressive to me that I firmly believe the stuff has to do something. It’s just a matter of figuring out dose and figuring out what scenarios the compound will be most useful in. So keep an eye out for this stuff. You surely be hearing about it more in the future. I think this stuff could be the “real deal”