The Myostatin <> Clenbuterol Connection - More Muscle, Less Fat: Is an Orphan Nuclear Receptor the Missing Link?

Image 1: Belgian Blue cattle are "naturally" myostatin negative. These beasts are 100% muscle 0% fat and though your usual clenbuterol fattened meatstock cannot compete, the heavily abused beta-2 agonist could infact work its muscle building, fat burning magic via very similar mechanisms.

You have probably heard at least one of the dozens of reports on clenbuterol in pork, chicken, beef and lately sheep meat from China, haven't you? I mean, that kind of meat, innocent Tour de France competitors consume and end up with a positive doping test ;-) "Clenbuterol?", some of you may now ask themselves: "Isn't that the illegal fat burner bodybuilders use to get totally shredded in the last weeks of their contest prep?" Well, you are right, but "lean meat powder" (CRJ. 2011), as our Chinese friends call it, has another, less known and hitherto not completely understood quality: Clenbuterol builds muscle! And while we did already know that these effects are mediated via its beta-2-adrenergic activity (Hinkle. 2002), the underlying mechanism of how "stress" (remember the main beta-2 agonist in the human body is noradrenaline) can induce muscle growth and prevent atrophy, have hitherto been obscure. With the recent publication of a studies on the metabolic (not myogenic, i.e. muscle-building) effects of myostatin and its inhibition by beta-2 agonists this may yet change...

The two studies, on which my argumentation will be based were published in the diabetes journal Diabetologia (Zhang. 2011) and the journal of the Endocrine Society, Endocrinology (Pearen. 2011). Zhang and his colleagues from Singapore have studied the effects of my all-time favorite high-fat diet (HFD; 60% of the calories from fat, but by no means "low carb") on myostatin-null mice,  mice fed with the type IIB receptor, sActRIIB, which binds and deactivates myostatin, and wild type mice - and I must say, their findings are quite exciting.

Figure 1: Relative weight gain (compared to baseline, left) and haematoxylin and eosin stained adipocytes from WAT (right) of wild-type and Mstn − /− mice after 12 weeks of chow diet and HFD treatment (adapted from Zhang. 2011).

Deletion or deactivation of myostatin, the TGF beta protein you probably associate with over-muscled, but clumsy and a few exceptions, such as the Belgian Blues in image 1, aside, usually not particularly lean "mutants", did not only prevent the additional +18% weight gain in the HFD group (despite almost identical nutrient intake, cf. figure 1), it also modulated the triglyceride content (-250%!) and size of the mouse adipocytes (cf. figure ,1 small images).

Figure 2: Relative increase in fatty ocid oxidation (compared to baseline, left) and decrease in non-esterified fatty acids of wild-type and Mstn − /− mice after 12 weeks of chow diet and HFD treatment (adapted from Zhang. 2011).

And if you look at the increase in liver and white adipose tissue (WAT) fatty acid oxidation, the consequent decrease in non-esterified fatty acids (NEFA) and the profound increase in body temperature in the myostatin knock-out mice (cf. figure 2), you must concede that this data could as well have come from a study on one of the beta-2-agonist such as the short acting salbutamol, levosalbutamol & metaproterenol and the long-acting beta-2 adrenergic agonists clenbuterol, salmeterol, formoterol & bambuterol. Zhang et al. emphasize that these fat-burning effects, of which further analyses revealed that they are mediated largely by "enhanced PPAR pathway signalling" and increased expression of mitochondrial uncoupling proteins (>4x PPAR-a; >12x UCP1, >6x UCP2 and >4x UCP3 in epididymal white adipose tissue of HFD myostatin-negative mice), go way beyond what we would see as "a secondary effect of the increased muscle mass observed in the myostatin-negative mice" and have a certain similarity to what we would see in brown (BAT), not white adipose tissue - mystatin inhibition, as the scientists phrase it in the title of their paper thusly "promotes a brown adipose tissue phenotype", or, put more simply, it makes the fat-storing white adipose tissue behave as if it actually was its fat-burning brown cousin ;-)

Clenbuterol <> NOR-1 <> Myostatin

Image 2: Alberto Contador knows about the "advantages" of Chinese fatstock (BBC. 2011)

To understand how all this relates to the Pearen study (Pearen. 2011), we have to look at a tangent of the study, which investigated the role of the orphan nuclear receptor NOR-1 in the beta-adrenergic cascade. As it turned out, NOR-1 is expressed in skeletal muscle in response to exposure to beta-2-agonists and does not only modulate fatty acid oxidation (as we would have expected), but also dose-dependently repressed the myostatin promoter. Put simply, beta-2-activation induced NOR-1 activity releases the "hypertrophy break" and may thusly explain the well-known muscle building "side-effects" of clenbuterol, albuterol and all the other Chinese "lean meat powders" ;-)

More than a word of caution!

Now, this would not the SuppVersity, if I did not conclude this post with a word of caution: Neither the (ab-)use of clenbuterol or ephedrine (which is a weaker beta-2 agonist, Yamahara. 1985) nor the myostatin-"binder" sActRIIB, which, by the way, rendered the wild-type mice similar resistant to diet-induced obesity as their genetically engineered myostatin-negative peers, constitute safe ways to get the muscular and fat-free physique of your dreams. Remember that before you throw away your grass-fed beef and begin importing Chinese fatstock ;-)