Pluripotent Stem Cells As The Target Of Androgen Action

PLURIPOTENT STEM CELLS AS THE TARGET OF ANDROGEN ACTION
by Nandi


Testosterone and other androgens are noted for exerting two well-known effects on body composition: skeletal muscle hypertrophy, and a reduction in fat mass. It may be that androgens work in a variety of ways to achieve these effects, but is it possible to formulate one hypothesis of androgen action that can explain both these phenomena? Here I’d like to summarize one such hypothesis put forth recently by Bhasin et al (1) that attempts to do just that.



EFFECTS OF ANDROGENS ON MUSCLE TISSUE


Classically, muscle hypertrophy has been attributed to an increase in the synthesis rate of skeletal muscle protein, including myosin heavy chain. However, this theory fails to explain two well-characterized features of the action of testosterone on skeletal muscle; namely an increase in the number of nuclei contained in muscle cells, as well as the observed increase in muscle satellite cells. In fact, since mature muscle cell nuclei are incapable of mitosis, an increase in satellite cell number is a necessary requirement for the observed increase in nuclei after androgen administration. This is because satellite cells act as donors of nuclei when they fuse with preexisting muscle cells and donate their nuclei to the hypertrophying muscle fibers.

In addition to the observed increase in muscle mass and decrease in fat mass after testosterone administration, an increase in bone mass has also been observed. It would be elegant if this feature of the action of androgens could also be incorporated into one unifying theory of androgen action, without invoking separate mechanisms for this effect.



EFFECTS OF ANDROGENS ON FAT MASS


In previous studies carried out by Bhasin et.al., administration of graded doses of testosterone was associated with a dose-dependent decrease in fat mass, both in the trunk and appendices and in the subcutaneous and deep compartments. Testosterone exerts several effects that may be responsible for these observations. Testosterone seems to limit lipid uptake into fat cells, possibly by its inhibition of the enzyme lipoprotein lipase. Testosterone also stimulates lipolysis partly by increasing the number of beta-adrenergic receptors, which activate the enzyme hormone sensitive lipase, which is responsible for mobilizing stored fat for use as fuel. Additionally, testosterone has been observed to inhibit the differentiation of preadipocytes into mature fat cells, capable of fat storage. Again, while it may be the case that testosterone exerts a myriad of actions on muscle, fat and bone, it would greatly simplify our understanding of testosterone’s effects if one unifying theory of androgen action could be formulated to explain the reciprocal effects of testosterone on muscle and bone on one hand, and fat cells on the other.



THE PLURIPOTENT STEM CELL HYPOTHESIS


In the current paper, the authors hypothesize that androgens control the fate of so called uncommitted pluripotent stem cells of mesodermal origin. Stem cells have the ability to differentiate into several classes of adult cells, depending on which stem cell genes are activated. For example, the body has only a finite supply of satellite cells able to contribute their nuclei to hypertrophying muscle tissue. Stem cells serve as a reservoir for new satellite cells, so the supply of satellite cells is not rapidly exhausted. The same stem cells also possess the ability to follow different lineages, some becoming for instance adipocytes. The authors propose that androgens skew the differentiation of these stem cells away from an adipogenic lineage, towards a myogenic lineage. In other words, under the influence of androgens, such stem cells evolve into muscle tissue instead of fat cells. This neatly explains why androgens both promote muscle growth, and inhibit fat accumulation. The beauty of the theory lies in its simplicity: instead of invoking a myriad of different actions for androgens in their control of body composition, only one mechanism is required.

The figure below summarizes the key elements of this hypothesis. Plus signs indicate effects promoted by testosterone, while minus signs indicate processes inhibited by testosterone. The diagram indicates how testosterone promotes the differentiation of stem cells into muscle tissue.


To test their hypothesis, the authors incubated pluripotent stem cells (specifically of the cultured lineage designated C3H10T1/2) with both testosterone and DHT and observed the effects. Commitment of these cells to the myogenic lineage (i.e. their eventual development into muscle tissue) is associated with increased expression of muscle specific transcription factors including MyoD, myogenenin, and myf5, with the eventual expression of MHC II in terminally differentiated cells. All of these factors were observed to increase in a dose dependent manner upon exposure to the androgens.

On the other hand, exposure of the stem cells to androgens decreased the number of adipocytes, downregulating such markers of adipogenic differentiation such as PPAR-gamma. The concentrations of androgens used in the experiment were well within the range found in the plasma of normal adult men. Supraphysiological concentrations of androgens resulted in even greater stimulation of muscle development, explaining at least in part how AAS (anabolic-androgenic steroid) use promotes muscle hypertrophy and leads to fat loss.


(1) Bhasin S, Taylor WE, Singh R, Artaza J, Sinha-Hikim I, Jasuja R, Choi H, Gonzalez-Cadavid NF. The mechanisms of androgen effects on body composition: mesenchymal pluripotent cell as the target of androgen action. J Gerontol A Biol Sci Med Sci. 2003 Dec;58(12):M1103-10