IGF-I lucidity ... the murky waters begin to clear?

THE INSULIN-LIKE GROWTH FACTOR-I (IGF-I) gene plays a critical role in numerous physiological aspects of skeletal muscle, including development, metabolic function, and postnatal muscle growth. Further, the manipulation of IGF-I expression may have promising therapeutic use for treating various disorders of skeletal muscle and metabolism. Unfortunately, due to the complexity of the IGF-I gene, we still have a very poor understanding of IGF-I and its role in muscle physiology. It is clear that a number of different forms of IGF-I are produced in various tissues throughout the body, and skeletal muscle specifically appears to have the ability to produce some of these forms depending on the loading conditions (1). The IGF-I gene contains six exons that can produce several different isoforms through alternative splicing. Exons 1 and 2 are interchangeable, with the use of exon 1 or 2 being dependent on which one of the two tissue-specific promoters is activated (1). Inclusion of exon 1 or 2 denotes the class of IGF-I (i.e., class 1 or 2, respectively). Exons 3 and 4 contribute to a large portion of the signal peptide, mature peptide, and a portion of the E-peptide (1). Exons 5 and/or 6 contribute to the remaining part of the E-peptide and constitute the splice variants typically seen in muscle (1). Specifically, the majority of IGF-I mRNA produced in muscle is a result of exon 4 and exon 6 spliced together with exon 5 removed (IA in rodents and in humans). However, variants can be produced that include exon 5. For example, in loaded muscle one variant produced includes exon 5 and results in a premature stop codon in exon 6 due to a shift in the open reading frame (termed IB in rodents and IC in humans) (1). IGF-I IB or IC, also called mechanogrowth factor (MGF), has been the subject of numerous investigations (4). These different isoforms of IGF-I only share 50% sequence homology at the amino acid level in the E-peptides region (1). With all these different forms of IGF-I, understanding the actions of IGF-I have proven to be elusive. However, the experimental techniques utilized by Barton et al. (2) in their study in this issue of the Journal of Applied Physiology have provided enlightening data that should serve as a means to enhance our understanding of IGF-I biology in skeletal muscle. Using different forms of the IGF-I gene delivered by AAV technology and coupled with a nonbiased screening approach, the authors were able to identified novel and confirm previously suspected IGF-I-sensitive targets. These data should help elucidate underlying conundrums that have plagued investigators who are trying to understand the mechanisms by which both endogenous and exogenous IGF-I affect muscle growth. Clearly, controversy has arisen concerning the mechanisms by which IGF-I may be mediating changes in muscle mass during mechanical loading (8). Previously published data have convincingly shown that mechanical loading of muscle results in increased expression and/or production of multiple different forms of IGF-I (5). However, the mechanisms affected by the IGF-I have resulted in some controversy among various labs (10). Here, provocative data from Barton et al. (2) demonstrate that matrix metalloproteinase 13 (MMP-13) was found to be sensitive to both forms of IGF-I. MMPs are known to be critical for remodeling of the extracellular matrix (ECM), which includes collagen function. Kjaer’s lab (7) has demonstrated alterations in collagen gene expression occur within muscle and tendon with increased mechanical loading of muscle. Further, MMP activation increases with mechanical load and concurrently with alterations in collagen tissue dynamics (6). Thus, when one considers that there is ECM located in the periand intramuscular regions of muscle, it should be expected that a dynamic interaction would exist between muscle and its surrounding connective tissue that would likely lead to cross talk among the tissue. Thus it is not unreasonable to suggest that the elevations in IGF-I production by the muscle during mechanical loading may be affecting collagen dynamics in a paracrine fashion. Indeed, Doessing et al. (3) recently suggested that the increased IGF-I seen after exogenous growth hormone administration is affecting collagen synthesis in muscle and tendon but not affecting fractional protein synthesis in muscle. So, perhaps the role of increased IGF-I expression with mechanical loading is to mediate changes with ECM, which is adapting concurrently with muscle hypertrophy. Another elusive fact of the different isoforms of IGF-I is the upstream mechanism of action, in that it has been unclear if the different forms of IGF-I utilize the same membrane-based receptor. For example, previous suggestions were made that MGF (i.e., IGF-I IB or IC) affected mechanisms that regulate skeletal muscle mass through means independent of the known IGF-I receptor (11). Barton et al. (2) address this issue by employing the MKR mouse, which is a transgenic mouse that expresses a dominant negative IGF-I receptor specifically in skeletal muscle. The skeletal muscle of the MKR mouse does not respond to exogenous or endogenous IGF-I (9). Here, Barton et al. (2) clearly demonstrate that IGF-I IA or IB (i.e., MGF) overexpression cannot increase muscle mass without a functional IGF-I receptor. These data indicate that in order for exogenous MGF to induced muscle hypertrophy it does in fact require a functional IGF-I receptor. However, surprisingly both forms of IGF-I were able to induce changes in mRNA expression without a functioning IGF-I receptor; however, at this time it is unclear if the source of the signal was actually the muscle or other nonmuscle cells that reside in the muscle (i.e., fibroblasts). Thus, by using a combination of sophisticated molecular tools, Barton et al. (2) have provided us with a substantial amount of knowledge that perhaps sheds light on the effects of increased IGF-I during mechanical loading and its role in muscle hypertrophy. Further, the data indicate that isoforms of IGF-I mediate the majority of their effects through the IGF-I receptor, in particular the ability to induce muscle hypertrophy when the IGF-I is delivered exogenously. Overall, these findAddress for reprint requests and other correspondence: E. E. Spangenburg, Univ. of Maryland, Dept. of Kinesiology, College Park, MD 21045 (e-mail: [email protected]). J Appl Physiol 108: 1032–1033, 2010; doi:10.1152/japplphysiol.00252.2010. Invited Editorial