Supraphysiological levels of GDF 11 induce striated muscle atrophy

Growth and differentiation factor ( GDF ) 11 is a member of the transforming growth factor β superfamily recently identified as a potential therapeutic for age‐related cardiac and skeletal muscle decrements, despite high homology to myostatin (Mstn), a potent negative regulator of muscle mass. Though several reports have refuted these data, the in vivo effects of GDF 11 on skeletal muscle mass have not been addressed. Using in vitro myoblast culture assays, we first demonstrate that GDF 11 and Mstn have similar activities/potencies on activating p‐ SMAD 2/3 and induce comparable levels of differentiated myotube atrophy. We further demonstrate that adeno‐associated virus‐mediated systemic overexpression of GDF 11 in C57 BL /6 mice results in substantial atrophy of skeletal and cardiac muscle, inducing a cachexic phenotype not seen in mice expressing similar levels of Mstn. Greater cardiac expression of Tgfbr1 may explain this GDF 11‐specific cardiac phenotype. These data indicate that bioactive GDF 11 at supraphysiological levels cause wasting of both skeletal and cardiac muscle. Rather than a therapeutic agent, GDF 11 should be viewed as a potential deleterious biomarker in muscle wasting diseases.