Persistent IGF-I overexpression in skeletal muscle transiently enhances DNA accretion and growth

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.