GDF11 increases with age and inhibits skeletal muscle regeneration
Open accessAbstract
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.
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The antibodies used in the two GDF11 studies did not distinguish monomeric from dimeric forms of myostatin and GDF11.
“Importantly, there are monomeric (12.5 kDa) and dimeric (25 kDa) forms of both myostatin and GDF11, which were not distinguished using the cross-reacting antibodies in these studies42,43.”
From The central role of muscle stem cells in regenerative failure with aging (2015) · cites this paper as [43]
Aged MuSCs show impaired activation.
“However, aged MuSCs have been reported to show impaired activation in multiple studies, suggesting that a defect in activation dynamics may also contribute to impaired regeneration (Brack et al., 2007; Cosgrove et al., 2014; Egerman et al., 2015; Gilbert et al., 2010).”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Egerman et al., 2015
Circulating systemic factors such as hormones and inflammatory markers can positively and negatively influence satellite cell activation.
“Circulating systemic factors, such as hormones and inflammatory marker, can positively and negatively influence satellite cell activation.”
From Potential Roles of n-3 PUFAs during Skeletal Muscle Growth and Regeneration (2018) · cites this paper as [115]
Circulating growth factors GDF11 and myostatin, as well as inflammatory markers TNF-α and IL-6, increase with age, impairing regenerative capacity of satellite cells in human skeletal muscle.
“For instance, circulating growth factors, such as GDF11 and myostatin, as well as inflammatory markers, such as TNF-α and IL-6, increase with age, impairing the regenerative capacity of satellite cells in human skeletal muscle [10,115].”
From Potential Roles of n-3 PUFAs during Skeletal Muscle Growth and Regeneration (2018) · cites this paper as [115]
The role of blood-borne factors in aging-associated physiological and behavioral alterations in the brain has garnered further credence and offers therapeutic promise.
“Although the definitive role of GDF11 in aging-induced vascular deficits was challenged by subsequent studies, the role of blood-borne factors in aging-associated physiological and behavioral alterations in the brain has garnered further credence and offers therapeutic promise (Castellano et al, 2015;Egerman et al, 2015).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Egerman et al, 2015
The definitive role of GDF11 in aging-induced vascular deficits was challenged by subsequent studies.
“Although the definitive role of GDF11 in aging-induced vascular deficits was challenged by subsequent studies, the role of blood-borne factors in aging-associated physiological and behavioral alterations in the brain has garnered further credence and offers therapeutic promise (Castellano et al, 2015;Egerman et al, 2015).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Egerman et al, 2015
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- Authors
- Egerman, M. A., Cadena, S. M., Gilbert, J. A., Meyer, A., Nelson, H. N., Swalley, S. E., Mallozzi, C., Jacobi, C., Jennings, L. L., Clay, I., Laurent, G., Ma, S., Brachat, S., Lach-Trifilieff, E., Shavlakadze, T., Trendelenburg, A.-U., Brack, A. S., & Glass, D. J.
- Affiliations
- Novartis (Switzerland) (CH)
- Massachusetts General Hospital (US)
- Corresponding author
- Glass, David J.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 22
- Issue
- 1
- Pages
- 164-174
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4497834
- OpenAlex
- W1888932721
- Cited by
- 527
- References
- 34
- Citations by year
- 2026: 20 · 2025: 20 · 2024: 27 · 2023: 33 · 2022: 37 · 2021: 46 · 2020: 55 · 2019: 60 · 2018: 59 · 2017: 64 · 2016: 72 · 2015: 34
- FWCI
- 33.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR060868, R01AR061002)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Rheumatology › GDF15 and Related Biomarkers
- Keywords
- GDF11, myostatin, skeletal muscle regeneration, aging, age-related sarcopenia, age-related frailty, Smad2/3 signaling, myogenesis, satellite cells, TGF-beta superfamily
- MeSH terms
- Aging, Animals, Cell Differentiation, Cell Line, Humans, Regeneration, Signal Transduction, Up-Regulation, Muscle, Skeletal, Bone Morphogenetic Proteins, Myoblasts, Mice, Rats, Growth Differentiation Factors, Myostatin
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