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Enhanced athletic performance on multisite AAV-IGF1 gene transfer coincides with massive modification of the muscle proteome.

ABSTRACT: 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.

SUBMITTER: Macedo A

PROVIDER: S-EPMC3277730 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Enhanced athletic performance on multisite AAV-IGF1 gene transfer coincides with massive modification of the muscle proteome.

Macedo Antero A Moriggi Manuela M Vasso Michele M De Palma Sara S Sturnega Mauro M Friso Giorgio G Gelfi Cecilia C Giacca Mauro M Zacchigna Serena S

Human gene therapy 20120126 2

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 determin ...[more]

PMID: 22017471

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Project description:ObjectiveType 1 diabetes is characterized by autoimmune destruction of ?-cells leading to severe insulin deficiency. Although many improvements have been made in recent years, exogenous insulin therapy is still imperfect; new therapeutic approaches, focusing on preserving/expanding ?-cell mass and/or blocking the autoimmune process that destroys islets, should be developed. The main objective of this work was to test in non-obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, the effects of local expression of Insulin-like growth factor 1 (IGF1), a potent mitogenic and pro-survival factor for ?-cells with immunomodulatory properties.MethodsTransgenic NOD mice overexpressing IGF1 specifically in ?-cells (NOD-IGF1) were generated and phenotyped. In addition, miRT-containing, IGF1-encoding adeno-associated viruses (AAV) of serotype 8 (AAV8-IGF1-dmiRT) were produced and administered to 4- or 11-week-old non-transgenic NOD females through intraductal delivery. Several histological, immunological, and metabolic parameters were measured to monitor disease over a period of 28-30 weeks.ResultsIn transgenic mice, local IGF1 expression led to long-term suppression of diabetes onset and robust protection of ?-cell mass from the autoimmune insult. AAV-mediated pancreatic-specific overexpression of IGF1 in adult animals also dramatically reduced diabetes incidence, both when vectors were delivered before pathology onset or once insulitis was established. Transgenic NOD-IGF1 and AAV8-IGF1-dmiRT-treated NOD animals had much less islet infiltration than controls, preserved ?-cell mass, and normal insulinemia. Transgenic and AAV-treated islets showed less expression of antigen-presenting molecules, inflammatory cytokines, and chemokines important for tissue-specific homing of effector T cells, suggesting IGF1 modulated islet autoimmunity in NOD mice.ConclusionsLocal expression of Igf1 by AAV-mediated gene transfer counteracts progression to diabetes in NOD mice. This study suggests a therapeutic strategy for autoimmune diabetes in humans.

Dataset Information

Enhanced athletic performance on multisite AAV-IGF1 gene transfer coincides with massive modification of the muscle proteome.

Publications

Enhanced athletic performance on multisite AAV-IGF1 gene transfer coincides with massive modification of the muscle proteome.

Similar Datasets

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