Growth Factors: Cutting Edge Pharmacologically Enhanced Athletes

Growth factors are the latest Gutting-edge drugs being used by pharmacologically advanced bodybuilders. There is also a trickle-down effect to other elite athletes. These drugs have been shown to have potent effects on muscle and connective tissue and may prove to be potent anabolic agents. In many cases combinations of these drugs act synergistically so that the combined effect of two or more of these drugs appears significantly greater than the effect of anyone of them.

Several athletes have told me of the effectiveness on muscle mass and strength of using several of the growth factors together with any or all of anabolic steroids, Gil and insulin or insulogenic compounds, thyroid and several other compounds. The following report of these growth factors is of necessity somewhat technical. In future issues, as more information becomes available, we may be able to evaluate these compounds more realistically and thus prepare reports that are more direct and easier to understand. Growth factors promote particular types of cellular growth, differentiation and migration and include S100 beta, brain-derived neurotrophic factor (BDNF), neurotrophin 4/5 (NT-4/5), ciliary neurotrophic factor (CNTP), transforming growth factor beta (TGF beta), platelet-derived growth factor-AB (PDGF-AB), leukemia inhibitory factor (CDF/LIF), insulin- like growth factors land Il (IGF), nerve growth factor (INGF), neurotrophin-3 (NT3), growth factor (EGF), acidic and basic fibroblast growth factors (aFGF, bFGF), endothelins (ET-2 and ET-3) and the heparin-binding growth-associated molecule (HB-GAM).

Although we do not have any direct proof, some of these compounds theoretically could have ergogenic effects on the musculoskeletal system. Certainly, several of these growth factors have been found to affect skeletal muscle cells both in vitro and in vivo. For example, epidermal growth factor (EGF) and bovine serum albumin (BSA) are both required for serum-free growth human skeletal muscle satellite cells (HMSC).

The presence of growth factor receptors on the target cell surface is a prerequisite for the growth factor to have an effect. The receptor is a protein, and it has an extracellular site that binds to the growth factor, A signal is then transmitted through the transmemhrane site into the intracellular sire, at which point tyrosine kinase is activated. The signal reaches nuclear DNA through intracellular pathways that we know little about, and them transcription leads to production of target protein or cellular division and proliferation, or both. The effect of growth factor relates both to its concentration and the sensitivity of the receptor.

In one study a decade ago it was found that fibroblast growth factor, epidermal growth factor and insulin added in combination to the culture medium in which normal human muscle was cultured caused a fourfold increase of the total number of nicotinic acetylcholine receptors (AChRs) and a 4.5-fold increase in AChR aggregation. These findings show that these three polypeptide growth factors exert a neutonal-like influence on cultured human muscle in regard to AChRs.

EGF

Epidermal growth factor, once known as urogastrooe, is the best known of the growth factors and is the latest fad among strength athletes. It was first detected in 1962 from extracts of the submaxillary glands of mice and was originally known as urogastrone. Various cell types are stimulated by EGf including fibroblasts and muscle cells. I3GP has been shown to have some insulin-like activity on amino acid transfer into muscle cells. However, this activity has been shown to be less than those of IGPI or insulin. While there are anecdotes of significant muscle mass increase and strength increase, there is no valid information yet available on the effectiveness or adverse effects of ECF.

There is some evidence to show that EGF may modulate androgen action, stimulate testicular function and increase endogenous serum testosterone levels. However, no studies have been done to show that any of this occurs in humans. There is also some evidence to show that the use of both IGF-t and EGF has an additive effect on protein synthesis.

bFGF

The fibroblast growth factors are a family of seven or more related polypeptides stimulating the proliferation and differentiation of a wide variety of cell lines during both embryonic and adult life stages.

It has recently been suggested that human and mouse fibroblast growth factor 11 (FGF- genes and their products are involved in skeletal muscle and connective tissue development (Coulier et al., 1994). Fihroblast growth factor (POP] accumulation appears to be augmented in hypertrophied tissue compared to control fibers. In addition, POP-like growth activity can he isolated from hypertrophied muscle. The function, in vivo, basal lamina-localized FGP in rat muscle is not known, but it is most probably related to increased satellite cell replication seen during normal fiber maturation, during work-induced hypertrophy and during regeneration. During hypertrophy we observe the appearance of new fibers in addition to the growth existing fibers. ft is hypothesized that muscle hypertrophy involves activation of satellite cells that may then fuse with existing fibers and also harm new fibers.

Basic fibroblast growth factor (bFGF) is important in wound healing and is angiogenic in several animal models. has also been suggested that it indirect]y stimulates angiogenesis in vivo by stimulating inflammation. Collectively, these data suggest that FOP may serve as an important mediator of controlled growth during peripheral nerve regeneration.

There is also some evidence that hPGF maybe important in enhancing testicular function, especially in spermiogenesis. It also has a role in thermogenesis. recent study has shown that bFGF plays an important role not only in the thermogenic function of brown adipose tissue (BAT) but also in BAT enlargement. It is thus possible that NE and insulin contribute to the growth of rat brown adipose cells (RBACs) and endothelial cells partly through bFOF production by an autocrine mechanism.

To elucidate the mechanism of BAT enlargement, one recent study investigated the effects of norepinephrine (NE) and insulin on the in vitro growth of RBACs and the capillary growth in axlgiogenesis in vitro using co-culture of bovine cells with insulin. Prom this study it seems possible that NE and insulin contribute to the growth of RBAC and endothelial cells partly through bFGF production by an autocrine mechanism, suggesting that both agonists play an important role Dot only In the thermogenic function of BAT but also in BAT enlargement.

TGF

TOP-beta (transforming growth factor-beta) is pleiotropic and stimulates proliferation in some types of cell, particularly in connective tissues, while inhibits proliferation of other types of cells such as lymphocytes and most epithelial cells, and it reverses the impairment of wound healing induced by glucorticoids.

Studies have shown that TOP-beta was an equally active and more potent stimulator of amino acid uptake than was tOP-I, and the stimulation was additive beyond the maximal response attained with lop-I, suggesting that the two act by different mechanisms. Thus, it appears that the actions of the various growth factors could be synergistic. The same study also found that TOP-beta had no effect on the binding of insulin-like growth factors to their receptors on the cell surface, and it had little or no effect on some actions of the IGFs. There was essentially no change in the suppression of proteolysis or the stimulation of cell proliferation by IGEs when TGF-beta was also added to the medium.

Endothelins

Endothelins are produced by endothetial and epithelial cells, macrophages. fibroblasts and many other types of cells. Their receptors are present in numerous cells, including smooth muscle cells, myocytes and fibroblasts. Evidence now suggests that the three isoforrns of endothelins (El-I and the other two related isopeptides, ET-2 and ET-3l regulate growth in several of these cells. Endothelin-l influences DNA synthesis, the expression of protooncogenes, cell proliferation and hypertrophy.

Adverse Effects

Although the above growth factors may be useful in a variety of clinical conditions and in understanding the muscle growth process at the molecular, cellular and tissue levels, with implications for development and aging, health, disease and adaptation, it has been postulated that several of the growth factors can have serious health consequences, including promoting asthma, atherosclerosis and cancer. In lesions of atherosclerosis, various cytoklnes and growth factors, which are generally not expressed in the normal artery, ate upregulated. Several of them, including PDGF, bPOI fiB-POE IGF-t, 11.-i and TOP-beta and TNF play key roles in atherogenesis by stimulating chemotaxis and proliferation of vascular smooth muscle cells and production of extracellular matrix substances such as proteoglycans, collagen and elastic fibers by those cells.

Epidermal growth factor, a potent mitogen and tumor promoter, is excreted in urine, permitting it to incubate with urothelial cells. Insulin-like growth factor t is a potent mitogen for breast cancer cells. A recent study has suggested that stimulants at the POP receptor (FOP and transforming growth factor alpha) may play a role in the airway smooth muscle hyperplasia in asthma.

In summary, while the various growth factors may indeed be anabolic and act synergistically with each other and with other anabolic drugs such as anabolic steroids and insulin, they have potentially life threatening side effects-especially in those individuals who may be genetically susceptible to their atherosclerotic, tumorogenic and asthmatic effects.