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INVITED EDITORIAL
Departments of Biomedical Science and of Medical Pharmacology and Physiology
Dalton Cardiovascular Institute
University of Missouri
Columbia, Missouri
e-mail: boothf{at}missouri.edu
In the commercial world, there is the Pepsi taste test to see if blinded individuals prefer Pepsi over Coke. Although not a perfect analogy, in the scientific world, insulin-like growth factor I (IGF-I) exists in multiple "flavors" of peptide sequences, and the question addressed by Barton's exciting paper (2) in this issue is which IGF-I flavor is better for skeletal muscle?
IGF-I, in its many forms, plays a critical role in development, growth, repair, and maintenance of skeletal muscle. IGF-I stimulates differentiation of cultured L6 myoblasts (6); immunohistochemical levels of IGF-I increase within satellite cells of regenerating muscle (10); IGF-I stimulates proliferation to a small degree and has a more pronounced stimulation of differentiation in primary cultured satellite cells (1); mechanical-overloaded muscle has an eightfold rise in IGF-I mRNA in rats devoid of growth hormone, providing evidence of an autocrine or paracrine role for IGF-I in skeletal muscle hypertrophy (5); and transgenic mice overexpressing a dominant negative IGF-I receptor specifically in skeletal muscle exhibit reduced muscle mass and hypoplasia from birth to 3 wk of age but then develop hyperplasia and continue to have a reduced muscle mass as they grow to adulthood (7).
In 1985, IGF-I was shown by Bell et al. (3) to contain two 3' sequences (Ea and Eb) in mouse liver mRNA that resulted from alternative splicing of a 52-base pair sequence in the E domain, which changes the reading frame resulting in different IGF-IEa and IGF-IEb peptides. In 1996, Geoffrey Goldspink (8) found that skeletal muscle subjected to stretch-induced hypertrophy upregulated IGF-IIEb mRNA in skeletal muscle and named it "mechano-growth factor" (MGF) because a mechanical stimulus had caused its increase. After extensive additional studies, summarized by Goldspink (8), he suggested that MGF is more effective in producing muscle hypertrophy than IGF-IEa because MGF is responsible for the initial activation of satellite (stem) cells, and thus he contends that MGF "‘kick starts’ the hypertrophy/repair process." However, controversy remains, mainly due to the lack of alternative approaches to compare various IGF-I isoforms. Using the gene-transfer technique of adeno-associated virus (AAV), Barton (2) directly tests the efficacy of IGF-IEa vs. MGF (termed IGF-IA and IGF-IB, respectively, in her paper; Table 1) in producing skeletal muscle hypertrophy. For simplicity of reading this commentary, terminology used by Barton (2) is employed (Table 1).
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Four months after AAV injections into the extensor digitorum longus muscle of 6-mo-old mice, only muscles with IGF-IA expressed from the injected AAV had hypertrophy (a 5% larger muscle). Thus, under the conditions (AAV gene transfer) used by Barton (2), neither the 2- to 3-wk- nor the 6-mo-old mice support the suggestion of Goldspink (8) that IGF-IB is more effective than IGF-IA in producing hypertrophy.
Rosenthal (12) has called for an elucidation of the signaling mechanisms of the different IGF-I isoforms. Barton (2) has answered, in part, this request. Four weeks after 2- to 3-wk-old mice had AAV injections, the relative phosphorylations of the IGF-I receptor, Akt, and ERK1/2 were greater for IGF-IB than IGF-IA (2). Indeed, IGF-IA did not increase the phosphorylation of ERK1/2. Barton's observation (2) that IGF-IB increases ERK1/2 phosphorylation supports the contention that IGF-B expression in C2C12 myoblasts could activate proliferation while IGF-IA preferentially enhances differentiation (8). IGF-I has been shown to activate myoblasts thorough ERK1/2 signaling (11) and, subsequently, to induce differentiation through phosphoinositol 3-kinase/Akt signaling (12). These results are further supported by time course data from other investigators. In response to bupivacaine-induced regeneration (8) or resistance exercise (9), the increase and peak of IGF-IB mRNA in skeletal muscle precedes IGF-IA mRNA's increase (consistent with IGF-IB's role in proliferation as muscle cell proliferation proceeds differentiation). Thus Barton's results (2) are important extensions of some of the notions presented by Goldspink (8).
The trend for hypertrophy to lessen from 2 to 4 mo postinjection with AAV expressing either IGF-IA or IGF-IB is reminiscent of an earlier report of an attenuation of gastrocnemius muscle hypertrophy in transgenic mice overexpressing IGF-I in skeletal muscle as they age from 1 to 18 mo of age (4). Interestingly, Akt phosphorylation in satellite cells was inverted from 1 mo of age (where transgenic IGF-I mice > wild-type mice) to 18 mo of age (transgenic IGF-I mice < wild-type mice) (4). A future research direction will need to compare the short-term vs. long-term benefits of IGF on skeletal muscle mass and to compare signaling cascades under such circumstances. Such information seems crucial to realize the therapeutic potential of IGF-I to increase muscle mass. Additional studies are also needed to determine why preferential engagement of ERK1/2 signaling by IGF-IB is associated with less hypertrophy, and whether this difference is due to IGF-IB's better activation of satellite cell proliferation? Finally, it will be of great interest to determine which IGF-I isoform is the best flavor for reinvigorating muscle health.
Note: commentary is limited to 12 references and author apologizes for omitted references.
REFERENCES
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  A H Manninen Hyperinsulinaemia, hyperaminoacidaemia and post-exercise muscle anabolism: the search for the optimal recovery drink Br. J. Sports Med., November 1, 2006; 40(11): 900 - 905. [Abstract] [Full Text] [PDF]
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