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1.3. GH–IGF-I and skeletal muscle
The effect of GH on skeletal muscle is an area of uncertainty that has resulted in abuse of the hormone in the athletic community and as an anti-aging hormone. Since Rudman described the positive effects of recombinant GH (rhGH) in healthy older men [35], the hormone has received world-wide attention, and anecdotal stories of amazing responses to the hormone have been used for financial gain. In response to this, recent scientific reviews of GH and its effects on skeletal muscle have described relatively modest effects of the hormone on anabolism [36, 37 and 38]. Although it is important for the scientific community to separate fact from popular account, the potential of the hormone should not be completely discarded in our attempts to stem its widespread abuse.
The most convincing evidence that GH can improve muscle strength and function can be found in the studies assessing the effects of rhGH in GH-deficient adults. Svensson and colleagues found that rhGH, when given to GH-deficient adults over five years, increased isometric and isokinetic knee flexor and extensor strength, in addition to improving hand grip strength [39]. They also found that women had less of an improvement in strength than did men, and that proximal muscle groups are more responsive to GH than are distal muscle groups [39]. Although these positive effects on skeletal muscle are well documented, the length of time taken for the effects to become evident (years), as opposed to the more dramatic effects of androgens (weeks and months), have meant that the anabolic response of skeletal muscle to GH has been classified as minimal.
The efficacy of GH replacement is far less convincing in older men and women. Blackman and colleagues found that rhGH, when given to older men and women for 26 weeks, with or without sex steroids, increased lean body mass and decreased fat mass, but had little effect on muscle strength [40]. Only the combination of GH and testosterone in older men increased muscle strength and maximal oxygen capacity marginally, whereas there was no significant change in women receiving GH and estrogen [40]. Moreover, the adverse effects of GH on glucose metabolism resulted in the development of diabetes and glucose intolerance in several subjects [40]. The enhanced insulin resistance is caused by GH stimulation of lipid substrate oxidation resulting in increased serum fatty acid concentrations [41]. In addition, GH did not further improve muscle strength when administered to children with burns undergoing a 12-week exercise training program, with and without GH administration [42]. Muscle strength was increased primarily by exercise [42].
Despite this minimal response of muscle to GH, it could still be an important contributor to muscle anabolism, because it does stimulate IGF-I synthesis in muscle [43 and 44]. In young men made hypogonadal by administration of a gonadotropin-releasing hormone (GnRH) agonist, rhGH, increased concentrations of IGF1 mRNA in muscle biopsy samples obtained from the vastus lateralis [43]. In older men, administration of rhGH for one month also increased IGF1 mRNA concentrations in vastus lateralis muscle biopsy samples [44]. IGF1 expression is associated with skeletal muscle hypertrophy, as best demonstrated by animal studies where the IGF1 gene is selectively overexpressed in skeletal muscle [45]. Moreover, one mechanism by which IGF-I causes skeletal muscle hypertrophy might be through the stimulation of satellite cell replication; that is, by accelerating the progression of cell division [46]. There are many different triggers for local IGF1 expression, including androgens [13 and 47], mechanical load [48] and exercise [49]. Chronic inflammation, as indicated by interleukin-6 synthesis, is thought to cause loss of physical function by inhibiting local IGF1 skeletal muscle expression [50]. As an added complexity, multiple splice variants of IGF-I are found in skeletal muscle in response to different stimuli. Goldspink has described an alternative splice variant of IGF-I named mechano growth factor (MGF) that is produced in response to muscular activity [51]. Following heavy resistance exercise in young and older men, the expression of mRNA encoding MGF was increased in the young men, but an IGF-I isoform (IGF-IEa), which is similar to hepatic endocrine IGF-I but synthesized in muscle, is not altered during the exercise bout [49]. Moreover, older men did not increase MGF synthesis in response to the exercise bout [49]. The increase in IGF1 mRNA expression in skeletal muscle is probably driven by increased transcription of the IGF1 gene [52]. Therefore, as more is understood about the mechanisms controlling the expression of IGF1 in skeletal muscle and the mechanisms whereby IGF-I stimulates muscle hypertrophy, improved paradigms of rhGH administration or protocols using GH in combination with other agents could still make GH an important anabolic hormone for skeletal muscle function.
1.3. GH–IGF-I and skeletal muscle
The effect of GH on skeletal muscle is an area of uncertainty that has resulted in abuse of the hormone in the athletic community and as an anti-aging hormone. Since Rudman described the positive effects of recombinant GH (rhGH) in healthy older men [35], the hormone has received world-wide attention, and anecdotal stories of amazing responses to the hormone have been used for financial gain. In response to this, recent scientific reviews of GH and its effects on skeletal muscle have described relatively modest effects of the hormone on anabolism [36, 37 and 38]. Although it is important for the scientific community to separate fact from popular account, the potential of the hormone should not be completely discarded in our attempts to stem its widespread abuse.
The most convincing evidence that GH can improve muscle strength and function can be found in the studies assessing the effects of rhGH in GH-deficient adults. Svensson and colleagues found that rhGH, when given to GH-deficient adults over five years, increased isometric and isokinetic knee flexor and extensor strength, in addition to improving hand grip strength [39]. They also found that women had less of an improvement in strength than did men, and that proximal muscle groups are more responsive to GH than are distal muscle groups [39]. Although these positive effects on skeletal muscle are well documented, the length of time taken for the effects to become evident (years), as opposed to the more dramatic effects of androgens (weeks and months), have meant that the anabolic response of skeletal muscle to GH has been classified as minimal.
The efficacy of GH replacement is far less convincing in older men and women. Blackman and colleagues found that rhGH, when given to older men and women for 26 weeks, with or without sex steroids, increased lean body mass and decreased fat mass, but had little effect on muscle strength [40]. Only the combination of GH and testosterone in older men increased muscle strength and maximal oxygen capacity marginally, whereas there was no significant change in women receiving GH and estrogen [40]. Moreover, the adverse effects of GH on glucose metabolism resulted in the development of diabetes and glucose intolerance in several subjects [40]. The enhanced insulin resistance is caused by GH stimulation of lipid substrate oxidation resulting in increased serum fatty acid concentrations [41]. In addition, GH did not further improve muscle strength when administered to children with burns undergoing a 12-week exercise training program, with and without GH administration [42]. Muscle strength was increased primarily by exercise [42].
Despite this minimal response of muscle to GH, it could still be an important contributor to muscle anabolism, because it does stimulate IGF-I synthesis in muscle [43 and 44]. In young men made hypogonadal by administration of a gonadotropin-releasing hormone (GnRH) agonist, rhGH, increased concentrations of IGF1 mRNA in muscle biopsy samples obtained from the vastus lateralis [43]. In older men, administration of rhGH for one month also increased IGF1 mRNA concentrations in vastus lateralis muscle biopsy samples [44]. IGF1 expression is associated with skeletal muscle hypertrophy, as best demonstrated by animal studies where the IGF1 gene is selectively overexpressed in skeletal muscle [45]. Moreover, one mechanism by which IGF-I causes skeletal muscle hypertrophy might be through the stimulation of satellite cell replication; that is, by accelerating the progression of cell division [46]. There are many different triggers for local IGF1 expression, including androgens [13 and 47], mechanical load [48] and exercise [49]. Chronic inflammation, as indicated by interleukin-6 synthesis, is thought to cause loss of physical function by inhibiting local IGF1 skeletal muscle expression [50]. As an added complexity, multiple splice variants of IGF-I are found in skeletal muscle in response to different stimuli. Goldspink has described an alternative splice variant of IGF-I named mechano growth factor (MGF) that is produced in response to muscular activity [51]. Following heavy resistance exercise in young and older men, the expression of mRNA encoding MGF was increased in the young men, but an IGF-I isoform (IGF-IEa), which is similar to hepatic endocrine IGF-I but synthesized in muscle, is not altered during the exercise bout [49]. Moreover, older men did not increase MGF synthesis in response to the exercise bout [49]. The increase in IGF1 mRNA expression in skeletal muscle is probably driven by increased transcription of the IGF1 gene [52]. Therefore, as more is understood about the mechanisms controlling the expression of IGF1 in skeletal muscle and the mechanisms whereby IGF-I stimulates muscle hypertrophy, improved paradigms of rhGH administration or protocols using GH in combination with other agents could still make GH an important anabolic hormone for skeletal muscle function.