Submitted to: Journal of Federation of American Societies for Experimental Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/24/2002
Publication Date: 11/15/2002
Citation: Fiorotto, M.L., Schwartz, R.J., Delaughter, M.C. 2002. Persistent IGF-I overexpression in skeletal muscle transiently enhances DNA accretion and growth. Journal of The Federation of American Societies of Experimental Biology. Journal of Federation of American Societies for Experimental Biology. 17(1):59-60. Interpretive Summary: A hormone called insulin-like growth factor I, or IGF-I, is essential for the normal growth of people and animals. Our goal was to determine the mechanisms by which this hormone regulates skeletal muscle growth, and the extent to which these processes may be age-dependent. We examined the pattern of muscle growth in genetically engineered mice, called transgenic mice, that expressed high levels of IGF-I in their skeletal muscles, and evaluated both male and female transgenic mice at different ages in comparison to control mice. We noted different responses in muscles with different fiber compositions. As there were gender differences in weight gain, we looked for IGF-I effects beyond the muscles, elsewhere in the body. Our results showed that the muscle mass of the transgenic mice was larger by 5 weeks of age, reaching a maximum at 10 weeks. The total DNA and RNA contents were greater in gastrocnemius muscle in transgenic than nontransgenic mice, a difference that peaked at 5 weeks of age. In transgenic mice, we found further effects on fat deposition and organ growth, which varied according to age and gender. Stimulation of DNA replication by IGF-I was the main factor that determined the greater muscle mass. While IGF-I has shown itself to be an appealing candidate for gene therapy in patients with muscle atrophy, our observations support the wisdom of being cautious in the use of this approach, since secondary effects cannot always be predicted.
Technical Abstract: Adult transgenic mice with muscle-specific overexpression of insulin-like growth factor (IGF)-I have enlarged skeletal muscles. In this study, we; 1) characterized the development of muscle hypertrophy with respect to fiber type, age, and sex; 2) determined the primary anabolic process responsible for development of hypertrophy; and, 3) identified secondary effects of muscle hypertrophy on body composition. Transgene expression increased with age and was present only in fibers expressing type IIB fast myosin heavy chain. Muscle masses were greater by 5 wk of age, and by 10 wk of age the differences were maximal despite continued transgene expression. Total DNA and RNA contents of the gastrocnemius muscle were greater for transgenic mice than for nontransgenic littermates. The differences were maximal by 5 wk of age, and preceded the increase in protein mass. The accelerated protein deposition ceased when the protein/DNA ratio attained the same value as in nontransgenic controls. Despite localization of IGF-I expression to muscle without changes in plasma IGF-I concentrations, genotype also modified the normal age and sex effects on fat deposition and organ growth. Thus, enhanced DNA accretion by IGF-I was primarily responsible for stimulating muscle growth. In turn, secondary effects on body composition were incurred that likely reflect the impact of muscle mass on whole body metabolism.