Supraphysiological levels of GDF11 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 GDF11 on skeletal muscle mass have not been addressed. Using in vitro myoblast culture assays, we first demonstrate that GDF11 and Mstn have similar activities/potencies on activating p‐SMAD2/3 and induce comparable levels of differentiated myotube atrophy. We further demonstrate that adeno‐associated virus‐mediated systemic overexpression of GDF11 in C57BL/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 GDF11‐specific cardiac phenotype. These data indicate that bioactive GDF11 at supraphysiological levels cause wasting of both skeletal and cardiac muscle. Rather than a therapeutic agent, GDF11 should be viewed as a potential deleterious biomarker in muscle wasting diseases. Synopsis Growth and differentiation factor (GDF) 11 is a recently suggested anti‐aging therapeutic despite its similarity to myostatin. Here, GDF11 is shown to cause wasting of both skeletal and cardiac muscle in vitro and in vivo . GDF11 is a potent inducer of SMAD2/3 activation and skeletal muscle atrophy in vitro . AAV‐mediated systemic overexpression of GDF11 induces a rapid cachexic phenotype that involves severe loss of skeletal and cardiac muscle mass. Equal expression of GDF11 and Mstn causes similar losses in skeletal muscle mass; however, Mstn does not affect heart mass. Differential cardiac phenotypes by GDF11 and Mstn may be due to differences in receptor preference. Graphical Abstract Growth and differentiation factor (GDF) 11 is a recently suggested anti‐aging therapeutic despite its similarity to myostatin. Here, GDF11 is shown to cause wasting of both skeletal and cardiac muscle in vitro and in vivo .