GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration

• Published in: Cell metabolism Vol. 22; no. 1; pp. 164 - 174
• Main Authors: Egerman, Marc A., Cadena, Samuel M., Gilbert, Jason A., Meyer, Angelika, Nelson, Hallie N., Swalley, Susanne E., Mallozzi, Carolyn, Jacobi, Carsten, Jennings, Lori L., Clay, Ieuan, Laurent, Gaëlle, Ma, Shenglin, Brachat, Sophie, Lach-Trifilieff, Estelle, Shavlakadze, Tea, Trendelenburg, Anne-Ulrike, Brack, Andrew S., Glass, David J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.07.2015
• Subjects: Aging; Animals; Bone Morphogenetic Proteins - blood; Bone Morphogenetic Proteins - genetics; Bone Morphogenetic Proteins - metabolism; Cell Differentiation; Cell Line; Growth Differentiation Factors - blood; Growth Differentiation Factors - genetics; Growth Differentiation Factors - metabolism; Humans; Mice; Muscle, Skeletal - physiology; Myoblasts - cytology; Myoblasts - metabolism; Myostatin - metabolism; Rats; Regeneration; Signal Transduction; Up-Regulation
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2015.05.010

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. [Display omitted] •GDF11 inhibits rather than helps muscle regeneration•A GDF11-specific immunoassay shows a trend to GDF11 levels increasing in human and rat sera•GDF11 blockade may be an appropriate treatment for muscle disease Previous studies showed that GDF11 decreases with age and that GDF11 treatment improves muscle regeneration. Egerman et al. carefully re-assess this hypothesis and discover that the previously used reagents to detect GDF11 are nonspecific and that GDF11 actually increases with age and has deleterious effects on aging skeletal muscle.