GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration

Abstract

SUMMARY Age-related frailty may be due to decreased skeletal muscle regeneration. The role of TGF-β molecules myostatin and GDF11 in regeneration is unclear. Recent studies showed an age-related decrease in GDF11 and that GDF11 treatment improves muscle regeneration, which were contrary to prior studies. We now show that these recent claims are not reproducible and the reagents previously used to detect GDF11 are not GDF11 specific. We develop a GDF11-specific immunoassay and show a trend toward increased GDF11 levels in sera of aged rats and humans. GDF11 mRNA increases in rat muscle with age. Mechanistically, GDF11 and myostatin both induce SMAD2/3 phosphorylation, inhibit myoblast differentiation, and regulate identical downstream signaling. GDF11 significantly inhibited muscle regeneration and decreased satellite cell expansion in mice. Given early data in humans showing a trend for an age-related increase, GDF11 could be a target for pharmacologic blockade to treat age-related sarcopenia.

Lifelong exercise, but not short-term high-intensity interval training, increases GDF11, a marker of successful aging: a preliminary investigation

“…It should be further noted that Egerman et al. (2015) used in vitro doses of 10–100 ng/mL, while both their data, and our data reported here, suggests circulating GDF11 in older males is 100–1000 pg/mL, an order of magnitude lower in concentration, possibly explaining the disparity of these findings.…”

“…However, it has also been noted that GDF11 may inhibit myoblast differentiation into mature myotubes in a myostatin‐like manner (Egerman et al. 2015), perhaps unsurprising, as the myostatin and GDF11 peptide share ~90% homogeneity. It should be further noted that Egerman et al.…”

In vivo GDF3 administration abrogates aging related muscle regeneration delay following acute sterile injury

“…Several members of the TGFβ family (Egerman et al, 2015) are known regulators of muscle regeneration, whose members are secreted by repair macrophages acting in a paracrine manner (Massague, Cheifetz, Endo, & Nadal‐Ginard, 1986; McPherron, Lawler, & Lee, 1997), including GDF3 (Varga et al, 2016). We selected GDF3 for a proof‐of‐concept experiment to evaluate whether the observed impaired phenotypic transition in macrophage phenotype from inflammatory to repair type (Patsalos et al, 2017) can contribute to age‐related delay in muscle regeneration.…”

Lack of evidence for GDF 11 as a rejuvenator of aged skeletal muscle satellite cells

“…rGDF8 reduced young SC numbers (Fig. 1B, P  <   0.05) consistent with published findings (Sinha et al ., 2014; Egerman et al ., 2015). However, we observed rGDF11 also tended to reduce young SC numbers ( P  < 0.05) in agreement with Egerman et al .…”

“…Recent papers indicate GDF11 is not decreased in the circulation of aged rodents or older humans and that GDF11 is actually deleterious toward muscle repair in mice (Egerman et al ., 2015; Rodgers & Eldridge, 2015). The experiments performed in Egerman et al .…”