AuPS Logo Programme
Contents
Previous Next PDF

Muscle hypertrophy and IGF-1 isoforms: is bigger better?

T. Shavlakadze,1 R. Chai,1 G.J. Pinniger,1 K. Maley,1 G. Grounds,1 N. Winn,2 N. Rosenthal2 and M.D. Grounds,1 1School of Anatomy and Human Biology, University of Western Australia, WA 6009, Australia and 2Mouse Biology Unit, EMBL Monterotondo Outstation, via Ramarini 32, 00016, Monterotondo, Rome, Italy.

Insulin like growth factor-1 (IGF-1) plays a central role in muscle hypertrophy and muscle wasting. IGF-1 exists as different isoforms due to different exon splicing (Shavlakadze et al., 2005). IGF-1 isoforms that initiate from exon 1 are termed Class 1 (C1) isoforms, while isoforms that initiate from exon 2 are termed Class 2 (C2) isoforms. It has been proposed that different IGF-1 isoforms have different biological effects and may act through different signalling pathways. Previous studies show that over-expression of the Class 1 IGF-1 Ea (IGF-1:C1) causes skeletal muscle hypertrophy, slows the rate of myofibre atrophy following denervation and delays onset of necrosis in skeletal muscles of dystrophic mdx mice. Novel strains of non-dystrophic (normal) and mdx transgenic mice that over-express the Class 2 IGF-1 Ea (IGF-1:C2) isoform have muscle specific increase in total IGF-1 levels (∼5 times higher compared to non-transgenic controls) and show more consistent muscle hypertrophy compared to the IGF-1:C1 mice.

Over-expression of the IGF-1:C2 resulted in a significant increase in quadriceps muscle mass in male and female IGF-1:C2 and mdx/IGF-1:C2 mice compared to their wild type littermates. Muscle hypertrophy in transgenic mice was more pronounced at 12 months of age compared to 3 months of age. Myofibre cross sectional area (CSA) was also examined in IGF-1:C2 and mdx/IGF-1:C2 mice. Average myofibre CSA was larger in IGF:C2 mice compared to the wild type littermates at both 3 and 12 months. In muscles from dystrophic mdx/IGF-1:C2 mice the average myofibre CSA was increased at 3 months but not at 12 months. The reduction in myofibre CSA in 12 month old mdx/IGF-1:C2 mice was due to myofibre splitting or branching. Diaphragm width was increased in 12 month but not in 3 month old male and female mdx/IGF-1:C2 mice. Despite the increased muscle mass, IGF-1:C2 did not increase specific force in muscles from non-dystrophic or mdx muscles and did not reduce myofibre necrosis in sedentary and treadmill exercised mdx mice. In adult (non-dystrophic and mdx) muscles, IGF-1:C2 over-expression does not coincide with the up-regulation of the Akt/mTOR signalling. However, striking activation of Akt signalling was observed in growing muscles of young 3 week old IGF-1:C2 mice. This study compared signalling activated by the C1 and C2 IGF-1 Ea isoforms and emphasized the impact of muscle growth. It also critically evaluated medically relevant scenarios where IGF-1 induced muscle hypertrophy might have beneficial effects.

Shavlakadze, T., Winn, N., Rosenthal, N. & Grounds, M.D. (2005). Growth Hormone and IGF Research 15, 4-18.