Giacca's team created mice loaded with extra copies of the muscle-boosting gene IGF-1, which codes for the protein insulin-like growth factor 1, by injecting its limbs with a virus that implants IGF-1 into muscle cells. They then tested the animals' endurance by recording how long they could swim before exhaustion. The doped mice swam for three times as long as mice that received the virus but not IGF-1.
Autopsies showed that the extra IGF-1 triggered the production of 10 times more protein than normal in the muscles. Giacca also saw activity soar in genes controlling energy production, contraction of muscles and respiration. Also detectable in the muscle were traces of the virus used to deliver the genes. However, the gene, protein and virus were undetectable in blood or urine from the mice
Human Gene Therapy - Enhanced Athletic Performance on Multisite AAV-IGF1 Gene Transfer Coincides with Massive Modification of the Muscle Proteome
The fictional superhero, Captain America, has enhanced endurance and enhance strength.
Progress in gene therapy has hinted at the potential misuse of gene transfer in sports to achieve better athletic performance, while escaping from traditional doping detection methods. Suitable animal models are therefore required in order to better define the potential effects and risks of gene doping. Here we describe a mouse model of gene doping based on adeno-associated virus (AAV)-mediated delivery of the insulin-like growth factor-I (IGF-I) cDNA to multiple muscles. This treatment determined marked muscle hypertrophy, neovascularization, and fast-to-slow fiber type transition, similar to endurance exercise. In functional terms, treated mice showed impressive endurance gain, as determined by an exhaustive swimming test. The proteomic profile of the transduced muscles at 15 and 30 days after gene delivery revealed induction of key proteins controlling energy metabolism. At the earlier time point, enzymes controlling glycogen mobilization and anaerobic glycolysis were induced, whereas they were later replaced by proteins required for aerobic metabolism, including enzymes related to the Krebs cycle and oxidative phosphorylation. These modifications coincided with the induction of several structural and contractile proteins, in agreement with the observed histological and functional changes. Collectively, these results give important insights into the biological response of muscles to continuous IGF-I expression in vivo and warn against the potential misuse of AAV-IGF1 as a doping agent.
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