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Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, and Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294; and Endocrinology Section, Medical Service, Veterans Affairs Medical Center, Birmingham, Alabama 35233
Address all correspondence and requests for reprints to: Dr. Stuart J. Frank, University of Alabama at Birmingham, 1530 3rd Avenue South, BDB 861, Birmingham, Alabama 35294-0012. E-mail: sjfrank{at}uab.edu.
GH is a 22,000-Da protein produced in multiple tissues but most notably by the somatotrophs of the anterior pituitary gland. In addition to important metabolic effects, GH has been known since the mid-20th century to enhance muscle mass and promote longitudinal growth. How GH exerts these somatogenic effects has been a major question in modern endocrinology. Seminal observations in the 1950s led Salmon and Daughaday to posit the "somatomedin hypothesis" of GH action (1, 2). As originally articulated, this hypothesis suggested that GH stimulated hepatic secretion of a factor known as somatomedin-C, which then functioned in an endocrine manner to promote growth at target tissues, such as muscle and bone. Somatomedin-C was later defined as an approximately 6000-Da peptide hormone, IGF-I, which conveyed its actions by binding to and activating the IGF-I receptor, a heterotetrameric tyrosine kinase-encoding receptor that triggers growth-promoting and antiapoptotic pathways. The strength of this hypothesis resided not only in its elegance, but also in the important work it spawned challenging it, especially in the past two decades; this has led to better understanding of the hormonal regulation of growth.
Unrestricted targeted deletion of the IGF-I gene, first reported in 1993, resulted in severe intrauterine growth retardation and a high degree of perinatal lethality (3, 4). IGF-I receptor gene deletion was uniformly fatal (4). These studies established the essential role of IGF-I in intrauterine growth and development but did not address the question of whether GH uses IGF-I (and, in particular, liver-derived IGF-I) as its mediator of postnatal growth. When later bred into a different mouse strain (5) or independently derived by other means (6), IGF-I unrestricted knockout mice achieved substantially better postnatal viability. These mice exhibited severe embryonic growth retardation but experienced almost no growth during the postnatal period, usually characterized by GH-dependent growth. Furthermore, endogenous GH levels were elevated and exogenous GH failed to cause growth (6), strongly suggesting that GH-mediated longitudinal growth depends highly on IGF-I. Interestingly, a common finding in these IGF-I deficiency models was an increase in relative liver size, suggesting that GH directly affects growth of some tissues, despite its apparent lack of effect on longitudinal growth (5, 6). The late 1990s brought elegant studies of the role of liver-derived IGF-I (7, 8). Liver-specific targeted IGF-I deletion (the "LID" mouse) resulted in an approximately 75% decrease in circulating IGF-I, marked (
4-fold) elevation of plasma GH, and no change in peripheral (nonhepatic) IGF-I mRNA levels, results consistent with the liver being the principal source of circulating IGF-I and liver-derived IGF-I being a major regulator of GH production (presumably via negative anterior pituitary feedback). Surprisingly, however, the LID mice grew normally without effect on body size, powerfully suggesting that hepatic IGF-I, despite being the main contributor to circulating IGF-I levels and regulating GH secretion, is not essential for normal postnatal growth. Furthermore, these data advanced the idea that autocrine/paracrine-derived IGF-I predominates for normal postnatal growth. However, breeding of the LID mouse with a mouse deficient in the acid-labile subunit of the IGF binding complex (the ALSKO mouse) resulted in destabilization and even further reduction (90%) of circulating IGF-I and significantly impaired postnatal growth, suggesting that reduction of circulating IGF-I, independent of its origin, below a threshold level does impact growth (9).
The paper by Klover and Hennighausen (10) in this issue extends these studies in an important and elegant fashion. The study builds on essential knowledge of GH action gleaned over the past two decades in parallel to the IGF-I studies referred to above. Most notably, we know from cell culture and mouse models that GH receptor (GHR) couples to the tyrosine kinase, Janus kinase 2 (11), and the latent transcription factor, signal transducer and activator of transcription (STAT)5 (12, 13, 14) and that generalized knockout of the GHR (15) or STAT5 (16, 17) leads to substantial growth reduction. Furthermore, GH promotes hepatic IGF-I gene expression largely via STAT5 activation (18, 19, 20, 21, 22), and GH treatment of myoblasts in culture activates STAT5 and causes IGF-I gene expression (23). Klover and Hennighausen (10) prepared a mouse lacking STAT5 (both the A and B isoforms) specifically in skeletal muscle (the STAT5MKO mouse). This resulted in dramatic reduction (60%) in skeletal muscle IGF-I mRNA content without change in liver IGF-I mRNA and only a modestly lower (15%) circulating IGF-I level. Remarkably, the STAT5MKO mouse manifested significantly reduced postnatal growth and skeletal size with markedly lower lean mass in both males and females. In contrast to knockout of STAT5 in muscle, selective deletion of STAT5 in liver (STAT5LKO) did not affect growth, and mice with STAT5 knockout in both muscle and liver (STAT5M/LKO) were indistinguishable in terms of their size from STAT5MKO mice.
Although the growth deficit was more modest in the STAT5MKO mice than in the unrestricted STAT5 knockout mice, these results suggest that muscle STAT5, presumably activated by GH (although this is not specifically shown) is a major contributor to body growth. Furthermore, the lack of an additive effect when STAT5 was also deleted in liver and the relatively modest decrease in circulating IGF-I strongly suggest that local (autocrine/paracrine) effects of IGF-I in the muscle predominate over endocrine IGF-I effects. These are important insights. Another interesting feature is that skeletal muscle is apparently communicating with nearby bone to exert its growth-promoting effect. How does this communication occur? Is it due to local circulation effects? What is the mediator and could it be muscle-derived IGF-I itself? These questions are quite relevant, especially in light of observations that targeted deletion of IGF-I receptor (thereby interrupting IGF-I signaling) in osteoblasts affects bone matrix mineralization but not linear growth (24). Could a mediator other than IGF-I be communicating effects from skeletal muscle to bone?
It is important to consider these findings also in the context of the recent report by Sotiropoulos et al. (25), in which GH signaling was shown to have profound effects on muscle mass, predominantly by promoting fusion of myoblasts with nascent myotubes. In in vitro assays, this GH effect was shown to be exerted in an IGF-I-independent fashion. These in vitro data appear to contrast with those obtained in vivo with the STAT5MKO mouse. Other than differences in experimental systems, it is worth noting that the results obtained with the STAT5MKO mouse could, in principle, relate to defective (STAT5-mediated) skeletal muscle GH action that is independent of the reduction in local IGF-I production. That is, GH may induce STAT5-dependent IGF-I production in muscle and STAT5-dependent muscle and bone growth effects that are coincident but unrelated. This possibility, unlikely as it seems, would be addressable by comparing growth in the STAT5MKO mouse with that of a mouse with muscle-specific deletion of IGF-I. Notably, the MKR mouse generated in 2001 by Fernandez et al. (26), in which a dominant-negative form of IGF-1R was transgenically overexpressed in skeletal muscle, exhibited a reduction in body length early in postnatal life that was eliminated by 5 wk (27); furthermore, exogenous GH increased the length of both wild-type and MKR mice, despite failing to increase the muscle weight of the MKR mice (28).
Thus, the work of Klover and Hennighausen (10) adds significantly to our knowledge of how GH and IGF-I orchestrate growth and at the same time raises interesting questions. It is conceivable that GH and IGF-I exert their growth-promoting effects in multiple fashions, even collaborating with each other (29, 30, 31) or contributing in independent, but overlapping, ways (32). We can be certain that future studies will build further on the edifice of the somatomedin hypothesis to allow better understanding of these interesting issues.
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Acknowledgments |
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Received January 17, 2007.
Accepted for publication January 19, 2007.
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