Circulating Growth Differentiation Factor 11/8 Levels Decline With Age

Abstract

Rationale Growth differentiation factor 11 (GDF11) and GDF8 are members of the transforming growth factor-β superfamily sharing 89% protein sequence homology. We have previously shown that circulating GDF11 levels decrease with age in mice. However, a recent study by Egerman et al reported that GDF11/8 levels increase with age in mouse serum. Objective Here, we clarify the direction of change of circulating GDF11/8 levels with age and investigate the effects of GDF11 administration on the murine heart. Methods and Results We validated our previous finding that circulating levels of GDF11/8 decline with age in mice, rats, horses, and sheep. Furthermore, we showed by Western analysis that the apparent age-dependent increase in GDF11 levels, as reported by Egerman et al, is attributable to cross-reactivity of the anti-GDF11 antibody with immunoglobulin, which is known to increase with age. GDF11 administration in mice rapidly activated SMAD2 and SMAD3 signaling in myocardium in vivo and decreased cardiac mass in both young (2-month-old) and old (22-month-old) mice in a dose-dependent manner after only 9 days. Conclusions Our study confirms an age-dependent decline in serum GDF11/8 levels in multiple mammalian species and that exogenous GDF11 rapidly activates SMAD signaling and reduces cardiomyocyte size. Unraveling the molecular basis for the age-dependent decline in GDF11/8 could yield insight into age-dependent cardiac pathologies.

GDF11 Protects against Endothelial Injury and Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Null Mice

“…significant dose-dependent decrease of heart weight, normalized to tibia length, after only 9 days of treatment in mice receiving 0.5 or 1.0 mg/kg/day GDF11. 9 In this study, we found that GDF11 improved endothelial dysfunction, decreased endothelial apoptosis in vivo and in vitro, and reduced atherosclerosis plaque including the en face and cross section areas as well as enhanced mature plaque stability in apoE −/− mice. Moreover, our human study showed that circulating GDF11/8 levels are positively associated with FMD in male overweight subjects.…”

“…However, other data showed that the increase of serum GDF11 in mice reported by Egerman et al is not GDF11 but predominantly immunoglobulin light chain (the ~25 kDa band by Western blot), immunoglobulins have long been known to increase with age in C57BL/6 mice. 9 They also found that circulating GDF11/8 levels decline with age in multiple mammalian species. In this study, we also found circulating GDF11/8 levels decline with age in mice and in male overweight subjects.…”

“…7,8 Very importantly, new data demonstrated that circulating growth differentiation factor 11/8 (GDF11/8) levels decrease with age in mice as well as other mammalian species and that increasing GDF11/8 levels with exogenous GDF11 regulates cardiomyocyte size. 9 Furthermore, a human study showed that plasma GDF11 concentrations declined with age in nondiabetic control subjects, 10 and the other two clinical reports revealed that higher GDF11 or GDF11/8 levels from large human cohorts are associated with lower risk of cardiovascular events and death, suggesting the GDF11 pathway as a potential new target to improve adverse cardiovascular outcomes associated with aging. 11,12 Thus, future studies are needed to prove the potential beneficial effects of GDF11 on age-associated cardiovascular diseases.…”

Glycogen distribution and metabolic alterations in the hypermuscular, myostatin mutant compact mice

“…The interaction of propeptide and myostatin is relevant in vivo, with a majority (Ͼ70%) of myostatin in serum bound to its propeptide (16). The amino acid sequence of GDF-11 (growth/differentiation factor-11) is 90% homologous to myostatin in the carboxy-terminal mature region of the protein, and like myostatin, GDF-11 can signal through ActRIIB (30), and GDF-11 administration leads to activation of Smad2 signaling (12,34). Myostatin propeptide may bind and inhibit GDF-11 as well as myostatin (30); therefore, the mutant propeptide of Compact mice might disturb not only myostatin but, e.g., GDF-11 signaling as well.…”

“…Detailed histological analysis showed that the myostatin KO (knock out) mice exhibit increased ratio of fast glycolytic, type IIB fibers with a concomitant decrease in oxidative type IIA and type I fibers in tibialis anterior and biceps femoris muscles [33]. Notably, this increased muscle mass is not accompanied by the proportionate increase in specific muscle force [34].…”