The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
Myostatin Knockout Drives Browning of White Adipose Tissue through Activating the AMPK-PGC1α-Fndc5 Pathway in Muscle
Open accessAbstract
Myostatin (Mstn) is predominantly expressed in skeletal muscles and plays important roles in regulating muscle growth and development, as well as fat deposition. Mstn-knockout (Mstn(-/-)) mice exhibit increased muscle mass due to both hypertrophy and hyperplasia, and leaner body composition due to reduced fat mass. Here, we show that white adipose tissue (WAT) of Mstn(-/-) develops characteristics of brown adipose tissue (BAT) with dramatically increased expression of BAT signature genes, including Ucp1 and Pgc1α, and beige adipocyte markers Tmem26 and CD137. Strikingly, the observed browning phenotype is non-cell autonomous and is instead driven by the newly defined myokine irisin (Fndc5) secreted from Mstn(-/-) skeletal muscle. Within the muscle, Mstn(-/-) leads to increased expression of AMPK and its phosphorylation, which subsequently activates PGC1α and Fndc5. Together, our study defines a paradigm of muscle-fat crosstalk mediated by Fndc5, which is up-regulated and secreted from muscle to induce beige cell markers and the browning of WAT in Mstn(-/-) mice. These results suggest that targeting muscle Mstn and its downstream signaling represents a therapeutic approach to treat obesity and type 2 diabetes.
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In the citing paper
“It contributes to the induction of PGC-1α, FNDC5, and irisin in SkM [27,49,133].”
In the citing paper
“Secreted FNDC5 then promotes the browning of WAT, establishing muscle–fat crosstalk that enhances energy expenditure and improves metabolic profiles [70].”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [70]
In the citing paper
“which in turn was due to the presence of the browning phenotype in the WAT, mainly because of an increase in the expression of irisin (Shan et al., 2013).”
From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Shan et al., 2013
In the citing paper
“On the other hand, knockout animals for myostatin presented not only an increase in muscle mass but also an improvement in composition due to a reduction of fat mass”
From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Shan et al., 2013
In the citing paper
“Importantly, the inhibition of myostatin signaling increases PGC1α and mitochondrial biogenesis 145, while mice deficient for myostatin show an improved metabolic phenotype and a resistance to HFD 146, 147.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [147]
Citations
Cites
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Beige Adipocytes Are a Distinct Type of Thermogenic Fat Cell in Mouse and Human
Wu, J., Boström, P., Sparks, L. M., Li, Y., Choi, J. H., Giang, A.-H., Khandekar, M. J., Virtanen, K. A., Nuutila, P., Schaart, G., et al. (2012) · Cell · doi:10.1016/j.cell.2012.05.016 · Cited by 3,406
FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis
Fisher, F. M., Kleiner, S., Douris, N., Fox, E. C., Mepani, R. J., Verdeguer, F., Wu, J., Kharitonenkov, A., Flier, J. S., Maratos-Flier, E., et al. (2012) · Genes & Development · doi:10.1101/gad.177857.111 · Cited by 1,478
Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice
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Myostatin, a Negative Regulator of Muscle Growth, Functions by Inhibiting Myoblast Proliferation
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Brown Remodeling of White Adipose Tissue by SirT1-Dependent Deacetylation of Pparγ
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Myostatin negatively regulates satellite cell activation and self-renewal
McCroskery, S., Thomas, M., Maxwell, L., Sharma, M., & Kambadur, R. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200207056 · Cited by 784
Research works printed but not linked: 1
- Tsurutani Y., 2009, Myostatin (MSTN) inhibits adipogenesis and high‐fat induced obesity via smad3: a possibility of crosstalk between muscle and adipose tissue, Diabetes, 58, A436
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Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway
Wrann, C. D., White, J. P., Salogiannnis, J., Laznik-Bogoslavski, D., Wu, J., Ma, D., Lin, J. D., Greenberg, M. E., & Spiegelman, B. M. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.09.008 · Cited by 1,440
Adipose tissue browning and metabolic health
Bartelt, A., & Heeren, J. (2014) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.204 · Cited by 1,177
Muscle wasting in disease: molecular mechanisms and promising therapies
Cohen, S., Nathan, J. A., & Goldberg, A. L. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4467 · Cited by 1,089
Exercise is the real polypill.
Fiuza-Luces, C., Garatachea, N., Berger, N. A., & Lucia, A. (2013) · Physiology · doi:10.1152/physiol.00019.2013 · Cited by 791
AMP-activated protein kinase: the current landscape for drug development
Steinberg, G. R., & Carling, D. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0019-2 · Cited by 785
Metadata
- Authors
- Shan, T., Liang, X., Bi, P., & Kuang, S.
- Affiliations
- Purdue University West Lafayette (US)
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2013-01-29
- Volume
- 27
- Issue
- 5
- Pages
- 1981-1989
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC3633817
- OpenAlex
- W2124205424
- Cited by
- 301
- References
- 49
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 15 · 2023: 16 · 2022: 30 · 2021: 28 · 2020: 20 · 2019: 26 · 2018: 19 · 2017: 26 · 2016: 21 · 2015: 30 · 2014: 31 · 2013: 18
- FWCI
- 23.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The FASEB Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Muscular Dystrophy Association
- National Institutes of Health
- U.S. Department of Agriculture
- Topics
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- myostatin, white adipose tissue browning, brown adipose tissue, AMPK, PGC-1α, FNDC5, irisin, beige adipocytes, skeletal muscle, non-cell-autonomous signaling, obesity, type 2 diabetes, UCP1, 4-1BB
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adenylate Kinase, Animals, Adipose Tissue, Brown, Fibronectins, Transcription Factors, Trans-Activators, Up-Regulation, Mice, Knockout, Muscle, Skeletal, Mice, Adipose Tissue, White, Myostatin
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