Reduced Circulating GDF11 Is Unlikely Responsible for Age-Dependent Changes in Mouse Heart, Muscle, and Brain

Recent high-profile studies report conflicting data on the age-related change in circulating growth/differentiation factor 11 (GDF11) and myostatin as well as the former's influence on muscle regeneration. Both ligands bind and activate ActRIIB receptors with similar affinities and should therefore have similar actions, yet these studies suggest that GDF11 activates muscle regeneration whereas myostatin is well known to inhibit it. They also suggest that circulating GDF11 levels, but not those of myostatin, decline with age. We performed a careful assessment of the ELISA used to quantify circulating myostatin in these studies and determined that assay reagents significantly cross react with each protein, each of which is highly homologous. Circulating myostatin levels decreased with age and estimates of GDF11 levels using myostatin null mice indicate that they were almost 500 times lower than those for myostatin. This suggests that circulating GDF11 has little physiological relevance as it could not outcompete myostatin for ActRIIB binding sites. Together, these results further suggest that the previously reported aging muscle, heart, and brain phenotypes attributed to reduced circulating GDF11 should be reconsidered.