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Skeletal muscle is an inherently plastic tissue. There is evidence to suggest that muscles are constantly adapting both in quantity and quality to the changing functional demands imposed by the types and amounts of physical activity routinely performed. To date, the evidence suggests that, in adults, activity induced adaptations of skeletal muscle are orchestrated by local—that is, tissue level as opposed to systemic—mechanosensitive mechanisms, which appear to include a number of growth factors and hormones. Of particular recent interest is the growth hormone (GH)/insulin-like growth factor-I (IGF-I) system. In the context of skeletal muscle homoeostasis, IGF-I is thought to mediate the majority of the growth promoting effects of circulating GH. In addition, it appears to function in a GH independent autocrine/paracrine mode in this tissue.1
As information on the mechanisms that modulate muscle adaptation has been elucidated in the scientific literature, it is tempting for athletes to apply this knowledge to enhance muscle mass and hence function by artificially manipulating these systems. In some cases, this has led to simplistic notions that exogenous anabolic agents can be used to safely and effectively stimulate or augment muscle. Unfortunately, many of these attempts have been unsuccessful, and, in truth, they ignore our understanding of the integrated nature of physiological systems.
The circumstances that militate against this approach are severalfold. The first and most obvious problem with anabolic substances is that they are invariably non-specific. Agents that can stimulate muscle cells to hypertrophy will undoubtedly have effects on other cells and tissues as well—for example, the impact of growth hormone on prostatic hypertrophy. Secondly, just as the body is made up of tissues and organs that function as an integrated whole, so muscle is comprised of a number of different cell types which must also function in unison. For example, a treatment that stimulates muscle cells to hypertrophy must also recruit fibroblasts to strengthen the connective tissues that will transmit the force generated by the muscle cells, and must also act to enhance angiogenesis and mitochondrial function. In the absence of this coordination, one may develop larger (therefore “stronger”) muscle cells, but the application of this enhanced contractile function would serve only to damage the structure of the muscle when the unenhanced connective tissue fails.
With regard to manipulating IGF-I either directly or through GH, a number of results from animal studies are instructive. Researchers have long sought ways to mitigate the atrophy inducing effects of unloading on skeletal muscle. An animal model used to study this effect involves “tail suspension” whereby rats are placed in cages with only their front feet touching any surface. This results in muscle atrophy which mimics that seen in humans following space flight. When GH or IGF-I has been supplied exogenously during tail suspension, the results have clearly indicated that the mass of the normally weight bearing muscles was in fact conserved. However, owing to the effects of these treatments on other tissues, the overall body weight of the rats had increased. It was as if the growth and development programme from an earlier developmental stage had been re-activated. However, there was one difference. When compared with their body weight changes, the muscles had actually “grown” less—that is, the normalised muscle mass was less in treated than untreated animals—the end result of course being that the growth factor treated rats would actually be less well adapted to normal ambulatory activity than the rats that received no treatment at all.
In humans, attempts to augment muscle mass using IGF-I have had less dramatic impacts. In studies designed to overcome the loss of muscle in the elderly, the overall impact of experimentally increasing circulating IGF-I levels has been negligible.9–11 For example, in one study the investigators managed to double the circulating IGF-I levels in elderly subjects but found no effect on the rate of protein synthesis in muscles; nor was there any augmentation of strength.11 In addition to this disappointing result, the supplementation of IGF-I in otherwise healthy—that is, GH normal—people is associated with (1) moderate to severe hypoglycaemia (it is after all insulin-like),6 (2) decreased growth hormone secretion,4,8 (3) a shift from lipid to carbohydrate oxidation for energy,8 and (4) a general disruption of the insulin/glucagon system.8,6 The issue of augmenting IGF-I is rendered even more complex because the biological activity of IGF-I in the body is now known to be substantially influenced by the family of IGF binding proteins.3 For example, recent work on the effects of hypoxia on rat growth suggests that it is, in fact, the impact of IGF binding protein-3 that is more closely related to overall growth than is IGF-I itself.7
There is also a more troubling aspect of IGF-I that has only recently begun to emerge. In addition to a direct anabolic effect on skeletal muscle—for example, the production of more protein—it has become clear that IGF-I is also capable of stimulating the proliferation and differentiation of muscle stem cells (satellite cells). In animal studies, there is evidence to suggest that this process is obligatory for muscle hypertrophy to proceed. However, this evidence that IGF-I is mitogenic should serve as a cautionary note to those who would use this agent to promote an anabolic state. There is increasing evidence to suggest that IGF-I signalling may also participate in cellular transformation.2 Specifically, elevated IGF-I levels have been linked to prostate, colorectal, and lung cancers.5
In the light of the large number of potentially negative impacts, ranging from disruption of the insulin system to cancer, it would seem that the exogenous augmentation of IGF-I does not represent a very attractive or effective method of increasing muscle mass or function. Clearly, the therapeutic use of these powerful growth factors awaits more focused research on the mechanisms through which these mediators actually influence growth in the context of the whole organism.
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