Abstract 12671: Growth Differentiation Factor-15 is an Akt1-Regulated Skeletal Muscle-Secreted Factor
Introduction: Wasting is a strong independent risk factor for mortality in patient with heart failure. We have recently demonstrated that increase in lean muscle mass can attenuate pathological cardiac remodeling in the setting of heart failure partly through production of skeletal muscle-derived angiogenic growth factors. Hypothesis: In addition to angiogenic growth factors, cardioprotective factors are secreted in response to skeletal muscle growth which in turn contributes to attenuation of detrimental cardiac remodeling.
Methods: We utilized skeletal muscle-specific, conditional Akt1 transgenic (TG) mice, that can induce the growth of functional skeletal muscle by switching Akt1 signaling on in muscle fibers. Adenovirus-mediated constitutive active form of Akt1 (myrAkt1) overexpression experiments were performed in C2C12 myoblasts. Akt1-mediated upregulated genes that contained signal sequence were searched by microarray analysis.
Results: Based on the microarray screening, we found that growth differentiation factor-15 (GDF-15), one of the members of TGFβ superfamily that has cardio-protective properties, was upregulated 5.3-fold in gastrocnemius muscle following Akt1 transgene induction (n=4, p<0.05). Akt1-mediated upregulation of GDF-15 transcript in the Akt1 TG mice was confirmed by quantitative real-time PCR (15.2-fold, n=6, p<0.01). GDF-15 protein expression was upregulated 2.5-fold in gastrocnemius muscle following Akt1 transgene induction. GDF-15-specific ELISA revealed that serum levels of GDF-15 were also increased in Akt1 TG mice compared with control mice. These results indicate that activation of Akt1 signaling in skeletal muscle leads to increase in circulating and tissue-resident GDF-15 levels. In vitro, GDF-15 transcript was upregulated in C2C12 cells treated with Adeno-myrAkt1. Myogenic Akt1 activation increased GDF-15 protein expression and secretion to culture media by 3.6- and 2.4-fold, respectively.
Conclusion: GDF-15 is an Akt1-regulated skeletal muscle-derived secreted factor. Stimulators of Akt1 signaling in skeletal muscle, such as resistance training, could attenuate cardiovascular diseases through secretion of muscle-derived cardioprotective factors.
- © 2012 by American Heart Association, Inc.