Muscle growth: no IGFs, ands, or buts (2008)

Over the past few years, news of positive drug tests, BALCO, and tarnished records have led many people to wonder whether it is possible to have sports without drugs. The crux of this question is whether it is possible to have muscle growth without the growth factor and hormone drugs that all too many athletes take. Increases in muscle size have largely been attributed to two factors: the mechanical load and the growth factor environment that the muscle experiences. However, the relative contribution of each factor is unknown. The difficulty in distinguishing between the two factors is one of the primary reasons that this question remains unanswered after almost 40 years of study. In the late 1960s, Goldberg conducted a series of studies on the role of insulin and other hormones on muscle growth (for review see Goldberg et al. 1975). In this work, he clearly showed that mechanical loading increased both protein synthesis and amino acid transport leading to muscle growth. Further, he demonstrated that muscle hypertrophy occurred in normal, diabetic, and hypophysectomized animals, suggesting that neither insulin nor pituitary hormones (primarily growth hormone) were required for adult skeletal muscle hypertrophy. While these experiments showed that systemic insulin and growth hormone were not required, they did not definitively rule out a role for growth factors, as locally produced growth factors may compensate for the absence of systemic insulin or growth hormone. Even with the advent of more sophisticated techniques, questions concerning the role of growth factors in muscle hypertrophy have persisted. Identification of a strong correlation between the magnitude of the load placed on a muscle, the activity of the mammalian target of rapamycin (mTOR), and muscle growth suggested that the mechanical load was the primary determinant of muscle growth (Baar & Esser, 1999). However, mTOR is also activated by many growth factors such as insulin and insulin-like growth factor 1 (IGF1) and muscle cells produce and secrete growth factors following mechanical loading that can activate mTOR and induce muscle growth in unstretched cells (Baar et al. 2000), suggesting that mechanical loading results in the production of autocrine factors that may play a role in the development of muscle hypertrophy. The finding that, in response to mechanical loading, muscle produces both IGF1 and a variant of IGF1 termed mechano-growth factor (MGF) provided strong support for this hypothesis (McKoy et al. 1999). Further, overproduction of IGF1 in muscle results in significant skeletal muscle hypertrophy (Coleman et al. 1995) leading many to hypothesize that mechanical loading increases muscle mass largely by increasing the autocrine production of IGF1 or an IGF1 related growth factor (Adams & Haddad, 1996). In an elegant study in this issue of The Journal of Physiology, Spangenburg et al. (2008) directly test this hypothesis. By virtue of their experimental design, the authors were able to distinguish between the effects of the mechanical load and the growth factors where others haven't by using a mouse line with muscles that cannot respond to either insulin or IGF1. As a result, they could directly determine the contribution of mechanical loading independently of systemic and autocrine growth factors. Since growth factors play an important role in developmental growth, the muscles of the transgenic mice were, as expected, smaller than wild-type controls. The surprise comes when the muscles of these animals are challenged with an increased load. Whereas the prevailing hypothesis would predict a diminished ability to grow, the muscles of the transgenic mice grow and activate mTOR to the same extent as wild-type controls. The implication is that the activation of mTOR and muscle growth is entirely dictated by the mechanical load the muscle experiences. If growth factors aren't required for the activation of mTOR or muscle growth, how is the mechanical signal transduced to a chemical signal that promotes hypertrophy (Fig. 1)? One possibility is that mechanical loading activates phospholipase D resulting in the activation of mTOR and muscle hypertrophy (Hornberger et al. 2006). However, this doesn't explain the activation of PKB/akt that occurs following resistance exercise. Another possibility is that mechanical loading overcomes the requirement for the growth factor receptor by altering the normal turnover of signalling molecules at the membrane. In this way, both PKB/akt and mTOR can be activated in the absence of growth factors. Schematic diagram of the signalling pathway associated with skeletal muscle hypertrophy Insulin and growth factors (GF) signal through the insulin receptor and its substrate (IRS1), whereas resistance exercise bypasses this receptor and activates protein kinase B (PKB)/akt independently of the insulin receptor. In both cases, the mammalian target of rapamycin (mTOR) is activated leading to protein synthesis via the protooncogene myc, the liberation of eukaryotic initiation factor (eIF) 4E from its repressor the eIF4E binding protein (4E-BP), and the activation of the 70 kDa ribosomal S6 kinase (S6K1). While growth factors and hormones are important developmentally in determining the size of our bodies, it is clear from the work of Spangenburg et al. that the primary stimulus for adult skeletal muscle hypertrophy is the mechanical environment. While this probably won't affect drug use among individuals seeking supramaximal muscle growth, for those of us that hold out hope, it suggests that hard work can increase muscle mass in the absence of external growth factors.